N-Thiazolylmethylthioalkyl-N&#39;alkylamidines and related compounds

ABSTRACT

N-alkyl-N&#39;-(2-aminoalkyl-4-thiazolylmethylthio)alkyl guanidines, thioureas, ethenediamines and related compounds, H 2  -receptor antagonists, useful in inhibiting gastric acid secretion in mammals.

CROSS-REFERENCE

This application is a continuation-in-part of my copending applicationSer. No. 193,192, filed Oct. 2, 1980 now U.S. Pat. No. 4,375,547, issued3/1/83.

BACKGROUND OF THE INVENTION

Over the past few years, several research groups in, chiefly, England orthe United States of America, have synthesized histamine H₁ or H₂-receptor antagonists. The H₂ -receptor antagonists are useful intreating peptic ulcers. Broadly speaking, these compounds can be classedas substituted amidines; e.g., acetamidine, ##STR1## Related compoundsinclude guanidines, ##STR2## mercaptoamidines or isothioureas, ##STR3##tautomeric with the thioureas ##STR4## and ethenediamines, ##STR5##tautomeric with ##STR6## In these new H₂ -receptor antagonists, theamidine usually occurs at one end of a bridging group; i.e., --CH₂--Y--(CH₂)₂ -- where Y is S, O, NH or CH₂. The other end of the bridginggroup has usually been an aromatic heterocycle, most frequentlyimidazole. The heterocyclic ring can be substituted.

The first drug recognized as a powerful H₂ -receptor antagonist was athiourea,burimamide--N-methyl-N'-(4-[4(5)-imidazolyl)]butyl)thiourea--having thefollowing formula: ##STR7## The pharmacological properties of thiscompound are disclosed in The Pharmacological Basis of Therapeutics,Goodman & Gilman 5th Ed. (MacMillan Publishing Co., Inc., New York) page612. Burimamide was developed by a group of research workers headed byBlack and Durant.

A second generation of histamine H₂ -receptor atagonists comprisedcompounds developed by Black, Durant and co-workers with a structuremore or less similar to that of burimamide, but in which there was apermissible interrupting group--oxygen, sulfur or NH--in the alkyl sidechain attached to the hetero ring. The most prominent of this group ofcompounds has been cimetidine, chemicallyN-cyano-N'-methyl-N"-[2-([(5-methyl-1H-imidazol-4-yl)methyl]thio)ethyl]guanidine,represented by the formula below: ##STR8##

A large number of patents based upon several original filings (Ser. Nos.230,451; 284,992; 385,027; 481,716; 816,420; 436,285; 542,971; 468,617;384,993; and 385,027) have issued to Durant et al including, but notlimited to, the following U.S. Pat. Nos. 3,950,333; 4,049,672;4,022,797; 4,137,237; 4,024,271; 4,070,475; 4,154,844; 3,905,984;4,027,026; 3,932,427; 4,018,928; 3,950,353; 4,053,473; 4,018,931;4,069,327; 4,151,288; 4,000,296; 4,083,988; 4,129,657; 4,098,898;4,166,856; 4,072,748; 3,971,786; 4,060,620; 3,876,647; 3,920,822;3,897,444; 3,975,530; 4,226,874; 4,228,291; 4,230,865; and 4,221,802.

Other disclosed hetero ring systems in addition to imidazole includepyrazole, pyridine, pyrimidine, pyridazine, thiazole, isothiazole,oxazole, isoxazole, triazole, thiadiazole, benzimidazole andtetrahydroimidazo[1,5-a]pyridine, but the greatest emphasis hascontinued to be placed on compounds having an imidazole ring system.Groupings which may be present at the terminal end of the alkyl oralkylthioalkyl bridging group include, among others, guanidine,cyanoguanidine, urea, nitroethenediamine and thiourea.

Patents referring to thiazole or oxazole ring systems are of particularrelevance to this invention. The two basic disclosures by the Durantgroup are contained in U.S. Pat. No. 3,950,333 and U.S. Pat. No.3,950,353, both of which are continuations-in-part of Ser. No. 290,584which was in turn a continuation-in-part of Ser. No. 230,451. In U.S.Pat. No. 3,950,333, the disclosure relating to thiazoles begins atExample 115, column 37. Thiazoles substituted with a chloro or an alkylgroup are described. The thiazole nucleus is then attached at the 2- or4- position of the thiazole ring to an alkylthioalkyl side chainterminating in an N-cyano-N'-methylguanidine. This disclosure isfollowed by similar disclosures for isothiazoles, oxazoles andisoxazoles. The disclosure in U.S. Pat. No. 3,950,353 relating tothiazoles begins at Example 110, column 37. Here, substantially the samethiazole nucleus is attached via a bridging group to anN-methylthiourea. A similar disclosure is present for isothiazoles,oxazoles and isoxazoles. U.S. Pat. No. 4,022,797, a division,specifically claims the cyanoguanidine derivatives and U.S. Pat. No.4,137,234, another division, specifically claims thioureas.

U.S. Pat. No. 4,000,296 discloses and claims a group of N-alkyl orN-arylsulfonyl-N'-alkyl-N"(heterocyclealkylthioalkyl)guanidines in whichthe heterocycle can be thiazole, isothiazole, oxazole or isoxazole.Alkyl, alkylaminoalkyl and alkyloxyalkyl bridging groups (connecting theheterocycle to the substituted guanidine group) are also disclosed.Substituted heterocycles belonging to any of the above classes are notdisclosed. U.S. Pat. No. 4,166,856, originating with the Durant group,discloses and claims a number of imidazoles and thiazoles carrying theusual alkylthioalkyl-guanidine, -thiourea or -ethenediamine side chain,which side chain is invariably attached at the 2-position of theheterocyclic ring.

Another group of investigators under Yellin has disclosed--see U.S. Pat.Nos. 4,165,377, 4,234,735 and 4,165,378--certain novel thiazoles havinga side chain such as those discussed above attached at the 4-position ofthe thiazole ring; i.e., an alkylthioalkyl-guanidine, -ethenediamine or-thiourea group attached thereto, but also bearing a guanidino group inthe 2-position of the thiazole. Alkylene, alkenylene and alkyloxyalkylbridging groups are also disclosed. A representative compound is2-guanidino-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazolewhich is said to have greatly increased activity over cimetidine.

A third research group at Allen and Hanburys Ltd. has prepared compoundswith a furan ring carrying the standard alkylthioalkyl (or alkyloxyalkylor alkyl) side chain terminating in a substituted guanidine orethenediamine group, and also having a dialkylaminoalkyl substituentattached at a second position in the furan ring--see U.S. Pat. Nos.4,128,658 and 4,168,855. Belgian Pat. Nos. 867,105 and 867,106 disclosethe corresponding thiophene and aminoalkylbenzenes. Several of thecompounds thus produced have a greater H₂ activity than cimetidine. Themost prominent of these is ranitidine ##STR9##

U.S. Pat. No. 4,233,302 from Glaxo also discloses a group of H₂-receptor antagonists having a dialkylamino alkyl substituted thiopheneor furan as one portion of the molecule.

Finally, a research group at Bristol-Myers have issued several U.S.patents involving different heterocycles. The first of these, U.S. Pat.No. 4,203,909, relates to furans carrying an alkylthioalkyl-guanidine(or thiourea or ethenediamine) side chain in the 2-position, anaminoalkyl side chain in the 5-position and an alkynylamino group aspart of the terminal portion of the molecule. One of the compounds,1-nitro-2-(2-propynylamino)-2-(2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino)ethylene,is said to have 7.45 times the activity of cimetidine in a standard H₂-receptor assay. A second patent, U.S. Pat. No. 4,200,578, coversbroadly thiazoles substituted with an alkylthioalkyl guanidine (orthiourea or ethenediamine) side chain, and again carrying an obligatoryalkynyl group in the terminal portion. Other permissible substituents inthe thiazole ring include alkyl, guanidino or aminoalkyl. Despite thebroad disclosure, the actual working examples in U.S. Pat. No. 4,200,578are limited to thiazoles carrying the alkylthioalkylguanidine, etc. sidechain in the 2-position of the thiazole ring except for a few compoundsin which the side chain is carried in the 4-position, but in which thereis an obligatory guanidino group in the 2-position. Synthetic Schemes Ithrough VIII of the patent are suitable only for preparing 2-substitutedthiazoles. Example 22 discloses thiazoles substituted in the 4-positionbut these thiazoles either do not carry a second ring substituent or, ifthere is one, it is a guanidino group.

U.S. Pat. No. 4,200,760 has a similar disclosure of an ethenediaminecarrying a alkynylamine group attached by a bridging group to animidazole ring. Pyridine is the heterocycle in U.S. Pat. No. 4,250,316.However, a recent Bristol-Myers Belgian Pat. No. 885,089, published3-4-81, same as U.K. Pat. No. 2,067,987, discloses a group of H₂-receptor antagonists among which are included compounds of the formula##STR10## One compound specifically disclosed is prepared from2-[2-(dimethylaminomethyl)-4-thiazolylmethylthio]ethylamine--See Example22, part E page 72 et seq.

To summarize, thiazoles in which there is a 4-alkylthioalkyl(oralkyl)-guanidine (or thiourea or ethenediamine) side chain are knownwherein the thiazole group can be substituted in the 2- or 5-positionwith guanidino, methyl, chloro and aminoalkyl. The disclosure relatingto thiazoles substituted with an aminoalkyl group at one position in thethiazole ring and, at a second position, a bridging alkylthioalkyl,alkylene, alkenylene or alkyloxyalkyl group terminating in a substitutedamidine group, is restricted to amidines carrying an N-alkynyl group aspart of the terminal grouping.

SUMMARY OF THE INVENTION

This invention provides compounds of the formula ##STR11## wherein eachof R¹ and R² independently represent hydrogen, (C₁ -C₄)alkyl, benzyl orbenzoyl; or taken together with the nitrogen atom to which they areattached, form a saturated heterocyclic ring containing from 5 to 7 ringatoms and 1-2 hetero atoms;

R³ is hydrogen or (C₁ -C₄)alkyl;

Z is O, S, or CH₂ ;

n is 2 or 3 when Z is O or S and n is 1, 2 or 3 when Z is CH₂ ;

R⁵ is hydrogen or (C₁ -C₄)alkyl;

m is 1, 2 or 3;

Q is ##STR12## wherein A is N--CN, N--NO₂, N--(C₁ -C₄)alkyl, CH--NO₂, S,O, NH, N--SO₂ -aryl, N--SO₂ --(C₁ -C₄)alkyl, N--CO--NH₂, N--CO--(C₁ -C₄)alkyl, N--CO₂ --(C₁ -C₄)alkyl; CH--SO₂ -aryl or CH--SO₂ --(C₁ -C₄)alkyl,wherein aryl is phenyl, halophenyl, (C₁ -C₄)alkylphenyl or (C₁-C₄)alkoxyphenyl; and

B is NRR⁶, wherein R is hydrogen, (C₁ -C₅)alkyl, (C₃-C₆)cycloalkylmethyl, hydroxy(C₂ -C₅)alkyl, (C₃ -C₆)cycloalkyl, (C₂-C₄)alkylene-N-[(C₁ -C₃)alkyl]₂ or (C₂ -C₄)alkylene-O-(C₁ -C₃)alkyl; R⁶is H or (C₁ -C₅)alkyl wherein the total number of carbons in R plus R⁶is less than 8; or

B is YR⁴, wherein Y is oxygen or sulfur and R⁴ is (C₁ -C₅)alkyl, --CH₂--(C₂ -C₄)alkenyl or benzyl; provided that when Q is ##STR13## B is NHRor O--(C₁ -C₂)alkyl; and acid addition salts thereof. Compoundsaccording to XX are particularly effective H₂ -receptor antagonists, orare useful intermediates in the preparation of such compounds.

Preferred compounds are those wherein R¹ and R² individually representhydrogen or (C₁ -C₃)alkyl, benzyl or benzoyl; in which one only of R¹and R² may represent benzyl or benzoyl and the other is (C₁ -C₃)alkyl;or wherein R¹ and R² taken together with the adjacent nitrogen atomrepresent a piperidino, pyrrolidino or morpholino group, provided thatonly one of R¹ and R² can be hydrogen when Z is CH₂ ; wherein R³ ishydrogen or (C₁ -C₃)alkyl; R⁵ is hydrogen or methyl; Q is ##STR14## A isN--CH, N--NO₂, N--(C₁ -C₄)alkyl, CH--NO₂, S, O, NH, N--SO₂ -aryl, N--SO₂--(C₁ -C₃)alkyl, N--CO--NH₂, N--CO--(C₁ -C₃)alkyl, N--CO₂ --(C₁-C₃)alkyl, CH--SO₂ -aryl or CH--SO₂ --CH₃, wherein aryl is phenyl,halophenyl, (C₁ -C₃)alkylphenyl or (C₁ -C₃)alkoxyphenyl; B is NRR⁶, R⁶is hydrogen; and R is as defined above; and thepharmaceutically-acceptable, non-toxic acid-addition salts thereof.

A preferred group of intermediate compounds have the same structuralcharacteristics except that B is YR⁴, Y is S and R⁴ is (C₁ -C₂)alkyl.

Further preferred features possessed by the H₂ -receptor antagonists ofthe invention are those listed below:

(a) Z is S;

(b) n is 2;

(c) R³ is hydrogen;

(d) R⁵ is hydrogen;

(e) m is 1;

(f) R¹ and R² are methyl;

(g) the ##STR15## group is dimethylaminomethyl; (h) A is NCN or CHNO₂ ;

(i) B is NRR⁶ where R⁶ is hydrogen and R is (C₁ -C₄)alkyl; and

(j) B is methylamino.

In Formula XX, when B is YR⁴, the grouping YR⁴ in general represents aleaving group such as methylthio, allylthio, or benzylthio. Othersuitable leaving groups will suggest themselves to those skilled in theart.

The presently preferred compounds of the invention are:

N-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-cyanoguanidine

N-methyl-N'-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-2-nitro-1,1-ethenediamine,and their pharmaceutically-acceptable salts.

Other bases of formula (XX) include:

N-ethyl-N'-2-[2-(2-dimethylamino)ethyl-5-methyl-4-thiazolylmethylthio]ethylguanidine

N-cyclopropylmethyl-N'-3-(2-methylethylaminomethyl-4-thiazolylmethylthio)propylguanidine

N-cyclohexyl-N'-2-(2-aminomethyl-5-n-propyl-4-thiazolylmethylthio)ethyl-N"-nitroguanidine

N-cyclobutylmethyl-N'-2-[2-(2-diethylamino)ethyl-4-thiazolylmethylthio]ethyl-N"-p-chlorophenylsulfonylguanidine

N-n-propyl-N'-2-(2-methylaminomethyl-5-methyl-4-thiazolylmethylthio)ethylthiourea

N-isopropyl-N'-3-[2-(2-ethylamino)ethyl-5-ethyl-4-thiazolylmethylthio]propylguanidine

N-ethyl-N'-2-[2-)2-diethylamino)propyl-5-methyl-4-thiazolylmethylthio]ethyl2-(o-bromophenylsulfonyl)-1,1-ethenediamine or1-(o-bromophenylsulfonyl)-2-ethylamino-2-(2-[2-(2-diethylamino)propyl-5-ethyl-4-thiazolylmethylthio]ethylamino)ethylene

N-cyclopentylmethyl-N'-2-(2-isopropylaminomethyl-4-thiazolylmethylthio)ethyl2-methane sulfonyl-1,1-ethenediamine

N-pentyl-N'-3-[2-(2-diethylamino)ethyl-5-propyl-4-thiazolylmethylthio]propyl2-nitro-1,1-ethenediamine.

N-(3-methylbutyl)-N'-2-(2-n-propylaminomethyl-5-ethyl-4-thiazolylmethylthio)ethyl2-o-tolylsulfonyl-1,1-ethenediamine

N-isobutyl-N'-2-[2-(ethyl-n-propylamino)methyl-5-n-propyl-4-thiazolylmethylthio]ethyl2-nitro-1,1-ethenediamine,

N-n-propyl-N'-2-(2-piperidinomethyl-4-thiazolylmethylthio)ethyl-N"-cyanoguanidine

N-methoxyethyl-N'-3-(2-aminomethyl-4-thiazolylmethylthio)propyl2-nitro-1,1-ethenediamine

N-(3-hydroxy)propyl-N'-4-(2-ethylaminomethyl-5-methyl-4-thiazolyl)-1-butyl-N"-cyanoguanidine

N-cyclobutylmethyl-N'-5-(2-dimethylaminomethyl-4-thiazolyl)-1-pentyl1,2-diamino-3,4-dioxo-1-cyclobutene or1-[5-(2-dimethylaminomethyl-4-thiazolyl)-1-pentylamino]-2-cyclobutylmethylamino-3,4-dioxo-1-cyclobutene

N-cyclopentyl-N'-2-(4-morpholinomethyl-5-ethyl-4-thiazolylmethloxy)ethylguanidine

N-cyclohexyl-N'-3-[2-(1-pyrrolidinomethyl)-4-thiazolylmethyloxy]propylurea.

N-cyclopropylmethyl-N'-3-[2-(2-methylamino)propyl-4-thiazolylmethyloxy]propylthiourea

N-dimethylaminoethyl-N'-3-[2-(2-ethylamino)ethyl-4-thiazolyl]propylguanidine

N-methyl-N'-3-(2-diethylaminomethyl-5-methyl-4-thiazolylmethyloxy)propyl-N"-nitroguanidine

N-isopropyl-N'-2-(2-di-n-propylaminomethyl-4-thiazolylmethylthio)ethyl-N"-methoxycarbonylguanidine

N-2-methylbutyl-N'-5-(2-diethylaminomethyl-4-thiazolyl)-1-pentyl-N"-acetylguanidine

N-n-butyl-N'-4-[2-(1-pyrrolidinomethyl)-4-thiazolyl]butyl-N"-aminocarbonylguanidine

N-methyl-N'-2-[2-(4-morpholinomethyl)-5-methyl-4-thiazolylmethylthio]ethyl2-nitro-1,1-ethenediamine

N-ethyl-N'-2-[2-(1-pyrrolidinomethyl)-4-thiazolylmethylthio]ethyl2-methanesulfonyl-1,1-ethenediamine and the like.

In Formula XX, the terms (C₁ -C₃)alkyl, (C₁ -C₄)-alkyl and (C₁ -C₅)alkylinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec.-butyl, t-butyl, n-amyl, isoamyl, 2-methylbutyl, 2-methyl-2-butyland the like radicals. Thus, the term (C₁ -C₃)alkylphenyl would includeo, m and p-tolyl, o, m, and p-ethylphenyl and the like. Similarly, theterm (C₁ -C₃)alkoxyphenyl includes o, m, p-anisyl, o, m, andp-ethoxyphenyl and the like. The term halophenyl includes o, m, andp-chlorophenyl, bromophenyl, fluorophenyl and iodophenyl. The term (C₃-C₆)cycloalkyl includes cyclobutyl, cyclopropyl, cyclopentyl,cyclohexyl, methylcyclopentyl and the like radicals. Heterocyclic ringswhich R¹ and R² plus the nitrogen to which they are attached representinclude pyrrolidine, piperidine, morpholine, thiomorpholine,4-methylpiperazine etc.

Illustrative of the alkoxyalkyl or dialkylaminoalkyl groups having lessthan a total of eight carbons, which R represents are 2-methoxyethyl,isopropoxyethyl, 3-ethoxy-2-methylpropyl, 2-(2propyloxyethyl)2-dimethlaminoethyl, diethylaminoethyl, 2-methylpropylamino-2-propyl andthe like.

The pharmaceutically-acceptable acid addition salts of the compounds ofthis invention include salts derived from non-toxic inorganic acids suchas: hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid,hydriodic acid, phosphorous acid and the like, as well as salts derivedfrom non-toxic organic acids such as aliphatic mono and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic andalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids,etc. Such pharmaceutically-acceptable salts thus include sulfate,pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, caprate,heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, mandelate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, benzenesulfonate, toluenesulfonate,chlorobenzenesulfonate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycollate, malate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate and the like salts.

Compounds according to XX above have at least one basic center, theaminoalkyl group at C-2 of the thiazole ring but may have a second orthird basic salt-forming group. For example, the substituted amidineterminal group can also have nitrogens present which are, depending onthe substitution pattern, sufficiently basic to form salts with thestronger nontoxic acids. Thus, di and tri salts of hydrochloric,hydrobromic and similar strong acids are preparable with many of thecompounds represented by XX.

The compounds of this invention wherein Z is S or O--in other words, aheteroatom--are conveniently prepared from a(2-aminoalkyl-4-thiazolylmethylheteroatom)alkyl amine. The preparationof these starting materials is illustrated in Flow Chart below using acompound in which the heteroatom is sulfur for exemplary purposes only.##STR16## In the above Flow Chart, alk is conveniently methyl or ethyland R¹, R², R³, R⁵, m and n have the same meaning as hereinabove.

In accordance with the above procedure, an acid addition salt of anaminoalkylthioacetamide (I) is reacted with a beta-bromo-alpha-ketoester(II) such as ethyl bromopyruvate (R³ =H) to yield an alkyl (methyl orethyl) 2-(aminoalkyl)4-thiazolecarboxyate (III). Reduction of this esterwith a suitable hydride reducing agent such as lithiumtriethylborohydride, lithium aluminumhydride, sodium borohydride,diisobutylaluminumhydride and the like yields the correspondinghydroxymethyl compound (IV). Reaction of the 4-hydroxymethylthiazolewith cysteamine or its higher homologue 3-mercaptopyropylamine in thepresence of acid yields directly a(2-aminoalkyl-4-thiazolylmethylthio)alkylamine (Va) optionallysubstituted with an alkyl group in the 5-position of the thiazole ring.

In the process indicated in Flow Chart A, in going from IV to Va, thehydroxymethyl group can be halogenated as with thionylchloride to yielda 4-chloromethylthiazole and the chlorinated compound in turn reactedwith the sodium salt of the particular mercaptoalkylamine. In fact, anystandard leaving group (a group liabile to nucleophilic displacement)can be employed here in place of chloro in the chloromethyl side chainincluding for example p-tosyloxy, mesyloxy (methanesulfonyloxy), bromo,iodo and the like.

Alternatively, the 4-chloromethylthiazole hydrochloride (or othersuitable acid addition salt) can be fused with a mercaptoalkylamine saltsuch as a hydrochloride salt to yield the desired primary amine(Va--Z=S).

If it is desired to prepare the side chain oxygen analogue of Va (Z=O),a process utilizing 2-chloroethylamine or 3-chloropropylamine to reactwith the 4-thiazolemethanol, under basic conditions, can be employed aswell as can the analogous Williamson ether process using the sodium saltof the hydroxyalkylamine with a 4-thioazolylmethyl halide.

Several pathways are available for preparing the compounds of thisinvention. These pathways or synthetic routes may utilize an amine ofthe generalized formula: ##STR17## wherein Z is S, O or CH₂, as astarting material. These routes are illustrated in Flow Charts B, C andD below. According to Flow Chart B, a starting primary amine, theultimate product of Flow Chart A (Va--Z=S), is reacted with, forexample, an N-alkyl, (cycloalkyl, cycloalkyl-substituted-alkyl,alkoxyalkyl or dialkylaminoalkyl) 1-methylthio-2-nitroethenediamine.During the reaction, the elements of methylmercaptan are displaced andthe final desired product (VIIa) is anN-2-(2-aminoalkyl-5-optionally-substituted-4-thiazolylmethylthio)alkyl-N'-alkyl(cycloalkyl, cycloalkylalkyl, alkoxyalkyl or dialkylaminoalkyl)2-nitro-1,1-diaminoethylene (or ethenediamine). Similarly, the primaryamine (Va) can be reacted with an S-methyl-N-alkyl (cycloalkyl,cycloalkylalkyl, alkoxyalkyl or dialkylaminoalkyl)-N'-cyanoisothioureato form the desired product (VIa)--an N-alkyl, (cycloalkyl,cycloalkylalkyl, alkoxyalkyl ordialkylaminoalkyl)-N'-2-(2-aminoallkyl-5-optionallysubstituted-4-thiazolylmethylthio)ethyl-N"-cyanoguanidine. ##STR18##wherein R¹ -R⁵, m and n have the same meaning as hereinabove, exceptthat both R¹ and R² can not be H.

In the above reactions, it is apparent that in place of an N-alkyletc.-1-methylthio- b 2-nitroethyleneamine, an N-alkyl tc.1-methylthio-2-methylsulfonylethyleneamine (or2-phenylsulfonylethyleneamine) could be used. If it is desired toprepare a compound of structure (XX) wherein Q is ##STR19## and A isN-SO₂ -phenyl, the reagent used to prepare suchN"-phenylsulfonylguanidines is dimethylN-phenylsulfonylimidothiocarbonate prepared by the general procedure ofBer., 99, 2885 (1966). The methylsulfonylguanidines are produced from adialkyl N-methylsulfonylimidodithiocarbonate prepared in the samefashion. Similarly, it is apparent that an N-alkyl, (cycloalkyl,cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl or dialkylaminoalkyl)1-methylthio-2-arylsulfonylethyleneamine (or2-methylsulfonylethyleneamine) could be used in place of the N-alkyletc.-1-methylthio-2-nitroethyleneamine of the above flow chart.2-Arylsulfonyl-1-methylthioethyleneamine, the intermediate containing asulfonyl group, can be prepared by reacting, for example, a2-arylsulfonyl-1,1-bis-methylthioethylene (prepared by the method ofBull., Soc. Chem. Fr., 637, (1973)) with one mole of an amine NH₂ R. The2-methylsulfonyl derivatives useful as intermediates can be prepared inthe same fashion.

Obviously, compounds corresponding to VI and VII in which O replaces Sin the bridging group are prepared by substituting a2-aminoalkyl-4-thiazolylmethoxyalkylamine for Va in Flow Chart B.

Thus, in the general case, compounds of formula (XX) in which B is NRR⁶may be prepared by reacting the amine intermediate of formula V with acompound of the formula L¹ QB where L¹ is a leaving group, preferablyfor ease of preparation, a C₁ -C₅ alkylthio, benzylthio or C₂ -C₄alkenylmethylthio group; Q and B being as previously defined.

The reactions of Flow Chart B should be effected in a polar solvent suchas water, a C₁ -C₄ alkanol or acetonitrile, preferably at a temperatureof from 20° to 100° C., most preferably 40° to 50° C.

An example of an alternate method of preparation of the compounds ofthis invention is illustrated in Flow Chart C. According to thisprocedure, the same requisite thiazole intermediate (V) is reacted witha 1,1-bis-methylthio-2-nitro (or arylsulfonyl or methylsulfonyl)ethylene to produce, where Z is S for example, anN-2-(2-aminoalkyl-5-optionally-substituted-4-thiazolylmethylthio)ethyl1-amino-1-methylthio-2-nitro (or arylsulfonyl ormethylsulfonyl)ethyleneamine. Compounds wherein Z is O or CH₂ areprepared similarly. ##STR20## wherein Z, R¹ -R⁵, m and n have the samemeaning as hereinabove, except that both R¹ and R² cannot be H.

According to Flow Chart C, reaction of the methylmercapto compound VIIIor IX with a primary amine NH₂ R yields the desired product.Illustratively, dimethylcyanodithioimidocarbonate will react with thethiazolylmethylthioalkylamine or other thiazolyl-side chain-amine (V) toproduce, for example, anN-2-(2-aminoalkyl-5-optionally-substituted-4-thiazolylmethylthio)ethyl-S-methyl-N'-cyanopseudothiourea(VIII where Z is S). Reaction of this compound with the primary amineNH₂ R again yields the desired product VI. Compounds in which A isCH--NO₂ etc. as in IX are prepared similarly and react similarly toyield an analogous final product having an ethenediamine terminal groupas in VII.

In going from V to IX, 1-methylsulfinyl-1-methylmercapto-2-nitroethylenecan be used in place of 1,1-bis-methylmercapto-2-nitroethylene to yieldthe same intermediate IX since a methylsulfinyl group is displacedpreferentially to a methylmercapto group.

Following the above procedure, in certain instances, a reactant such asVIII can be employed in which an OCH₃ group replaces the SCH₃. Thismethoxy group is replaceable by the amine NH₂ R as is the S--CH₃ groupillustrated above. For example, a compound of the formula (CH₃ O)₂--C═NCN can be employed, or a compound with two different leaving groupssuch as ##STR21## can be employed.

Thus, in the general case, a compound of formula: ##STR22## where L² isa leaving group, preferably a group of formula YR⁴, can be reacted withan amine of formula HNRR⁶ to yield compounds of formula XX.

The reaction is preferably effected at a temperature from 20° to 100° C.in a polar solvent such as water or a (C₁ -C₄)alkanol.

A third type of formula XX compound coming within the scope of the aboveformula are the thioureas or ureas wherein A is Y. An example of thepreparation of such compounds is illustrated in Flow Chart D. ##STR23##wherein R, R¹, R², R³, R⁵, Y, Z, n and m have their previously assignedmeanings, but only one of R¹ and R² can be H in a given molecule.

The above procedure can be generalized to use a reagent of the structureR--N═C═A to react with V to produce X. Where A is N--R, the reagent is acarbodiimide; where A is CH--NO₂, the reagent is a nitroketeneimine.

According to Flow Chart D, the starting amine, (V), for example athiazolylmethylthioalkylamine (Z═S), is reacted with a suitablysubstituted isothiocyanate to yield directly the isothiourea (X) whichcompound is in equilibrium with the thiourea itself (XI). Similarly, anisocyanate, R--N═C═O, can be used to prepare the corresponding urea.

In the general case, compounds of formula (XX) in which Q is C═A, and R⁶is hydrogen, may be prepared by reacting a compound of formula (V) witha reagent of the formula

    R--N═C═A

The reaction is preferably effected in a polar solvent such as water, a(C₁ -C₄)alkanol or acetonitrile. When A is oxygen, the reaction shouldnormally be effected in acetonitrile. Preferred reaction temperaturesrange from 20° to 100° C., most preferably from 40° to 50° C.

Compounds according to XX above in which Q is a3,4-dioxo-1,2-cyclobutenediyl radical can be prepared in a fashion moreor less analogous to the preparation of the corresponding ethenediaminesof Flow Chart C, in that the bivalent molecule,1,2-dimethoxy-3,4-dioxocyclobutene, can be reacted with a2-aminoalkyl-4-thiazolylmethylthio(or oxy)alkyl amine to yield a1-[2-aminoalkyl-4-thiazolylmethylthio(oroxy)]alkylamino-2-methoxy-3,4-dioxocyclobutene. This latter compound canthen in turn be reacted with an amine, NHRR⁶ to yield a compound offormula XX in which B is NRR⁶.

Compounds according to the above formula wherein B is NH₂ (R and R⁶ areboth H) and A is NCN can be prepared by a special reaction according toFlow Chart E. ##STR24## wherein R¹, R², R³, R⁵, Z, n and m have thenpreviously assigned value except that R¹ and R² cannot be H.

In this procedure, dicyanamide, usually generated in situ from one ofits salts, preferably the sodium salt, is reacted with a thiazolylprimary amine (V) to yield the cyanoguanidine (XII) directly.

Compounds according to Formula (XX) above wherein A is N--CO--NH₂ ;i.e., having a terminal group of the structure ##STR25## are prepared byhydration of the corresponding cyano compound, ##STR26## in dilutemineral acid such as, for example, dilute aqueous hydrochloric acid.

Finally, many of the compounds of this invention can be readily preparedvia a carbodiimide intermediate as illustrated in Flow Chart F.##STR27## wherein R--R⁴, Z, n and m have their previously assigned valueexcept that only one of R¹ and R² can be H, and R⁷ is CN, CO(C₁-C₃)alkyl, CO₂ (C₁ -C₃)alkyl, SO₂ -aryl or SO₂ CH₃ wherein aryl isphenyl, halophenyl, (C₁ -C₃)alkylphenyl or (C₁ -C₃)alkoxyphenyl.

According to Flow Chart F, an isothiourea VIIIa (prepared by theprocedure of Flow Chart C or equivalent procedure) is reacted withsilver nitrate to prepare a carbodiimide (XIII), reaction of which witha primary amine, RNH₂, yields those compounds of this invention whereinA is NCN etc. (VI).

In the general case compounds of formula XX, where Q is C═A and B isNHR, can be prepared by reacting a compound of formula: ##STR28## withan amine of formula RNH₂.

Compounds of formula XX wherein Z is CH₂ and n is 1, 2 or 3, can beprepared by the procedure illustrated in Flow Chart G below. ##STR29##wherein R¹, R², R³, R⁵, n and m have their previously assigned meaning,but only one of R¹ and R² can be H.

According to flow chart G, an omega (phthalimido)alkyl halomethyl ketone(XVI) is reacted with a dialkylaminothioacetamide hydrochloride toproduce a2-aminoalkyl-5-permissibly-substituted-4-omega-(phthalimido)alkylthiazole(XVII).The phthalimido group is removed by hydrazinolysis with hydrazinehydrate to produce the 4-(omega-aminoalkyl)thiazole (Vc). Alkalinehydrolysis with an alkali metal hydroxide followed by treatment with adilute hydrochloric acid can also be used. This primary amine product(Vc) corresponds to the starting material (Va) produced by flow chart Aand can undergo each of the reactions set forth in Flow Charts B-F toproduce the compounds of this invention wherein Z in formula XX is CH₂.

In the above reaction schemes, the aminoalkyl group present at position2 of the thiazole ring has been shown as carrying through each of thereaction steps essentially unchanged from the starting material employed(I in Flow Chart A). At times it is desirable to use certain alternateprocedures in those instances where either R¹ or R² or both arehydrogen. For example, where R¹ is hydrogen but R² is alkyl, it ispossible to use a benzyl protecting group through a given reactionscheme to the preparation of the primary amine derivative (Va) at whichpoint the benzyl group can be removed by catalytic hydrogenation to givea secondary amine grouping NHR². Similarly, an acyl protecting group canbe used such as a benzoyl group and this protecting group is removed byreduction to an alcohol during the lithium triethylborohydride reductionstep by using excess borohydride. Similarly, if it is desired to have aprimary aminoalkyl group at position 2 of the thiazole ring, aprotecting group such as a phthalimido group can be utilized. In suchinstance, the starting material (I) would be one in which R¹ and R²,when taken together with the nitrogen to which they are attached, form aphthalimido group. This grouping can be carried throughout the syntheticprocedure until it is desired to remove it (after reaction of theethylamine to form the side chain) by hydrazinolysis or other hydrolyticprocedure. Such a protecting group would be particularly valuable inthose instances where it is desired to utilize a 4-chloromethylthiazoleas an intermediate and to prepare such intermediate by the action ofthionylchloride. In the preferred synthetic procedure set forth in FlowChart A, use of such protecting groups for a secondary aminoalkyl groupat position 2 of the thiazole ring is not necessary.

An alternate procedure for preparing intermediates useful in thesynthesis of compounds of this invention (XX) starts with the reactionof dichloroacetone and a substituted aminothioacetamide. The use of theresulting 4-chloromethylthiazole where not more than one of R¹ and R² isH has been discussed previously in connection with Flow Chart A.However, this procedure is illustrated in Flow Chart H below and isparticularly valuable in preparing the compounds of this inventionwherein both R¹ and R² are H. ##STR30## wherein R, R⁵, A, m and n havetheir previously assigned significances.

In Flow Chart H, a 2-(phthalimidoalkylthioacetamide) reacts withdichloro acetone, following the procedure of J. Am. Chem. Soc., 64, 90(1942), to yield a 2-(phthalimidoalkyl)-4-chloromethylthiazole. Reactionof this intermediate with a cysteamine (or homocysteamine) derivative inwhich the amine group is substituted so as to form a desired terminal"amidine" provides a 2-(phthalimido)-4-thiazolyl derivative XVIII whichcan be hydrolyzed with hydrazine to yield the 2-aminoalkylthiazolederivative XXa in which R¹ and R² are H, and A and R have their previousscope.

This procedure constitutes a general method of preparing compounds offormula XX in which Z is sulfur. Thus, a salt of a compound of theformula: ##STR31## where L³ is a good leaving group, such as halo,preferably chloro; ester, for example, tosyloxy, brosyloxy or mesyloxy;or hydroxy, can be fused with a thiol of formula

    HS(CH.sub.2).sub.n --NH--CA--NRR.sup.6.

This fusion reaction does not require a solvent and can be effected attemperatures from 60° to 130° C., preferably 90° to 100° C.

In Flow Chart H above, a process is illustrated in which a leavinggroup--chloro--is present on the 4-thiazolemethyl moiety and the thiolgroup on, for example, a 1-[2-mercaptoethyl (or 3-mercaptopropyl)aminosubstituted]-1-alkylamino-2-nitroethenediamine or N-2-mercaptoethyl (or3-mercaptopropyl)-N'-cyano-N"-alkylguanidine. Alternatively, the leavinggroup can be present in the ethenediamine or cyanoguanidine moiety andthe thiol group present as such or as a pro-SH group in thedialkylaminoalkylthiazole portion, as illustrated below. ##STR32## whereR⁹ is SH or ##STR33## and R, R¹, R², R⁵, R⁶, m, n, A and L³ have thesame meaning as hereinabove. L³ is preferably Cl or Br, A is preferablyCH--NO₂ and R⁹ is preferably SH.

One starting material for the above synthesis is prepared by reactingthe desired 4-chloromethyl-2-aminoalkylthiazolehydrochloride or othersuitable salt (see discussion following Flow Chart A for preparation)with thiourea. The other starting material where A is CH--NO₂ isdisclosed in Belgian Pat. No. 886,997 and where A is N--CN, in U.S. Pat.No. 4,093,621.

In the above structures, the guanidines and ethenediamine terminalgroups have been written with structures K and L since it has beenbelieved that these are the most probable structures ##STR34## However,as is recognized in the art, K and L represent only one of threepossible tautomeric structures, the others being K', K", L' and L".##STR35##

In the above formulas R¹, R², R³, R⁴, R⁵, Z, m and n have the samemeaning previously assigned, R⁷ is NO₂, SO₂ --CH₃ or SO₂ -aryl and R⁸ isCN, NO₂, (C₁ -C₄)alkyl, SO₂ -aryl, SO₂ -(C₁ -C₄)alkyl, CONH₂, CO--(C₁-C₄)alkyl or CO₂ --(C₁ -C₄)alkyl wherein aryl is phenyl, halophenyl, (C₁-C₄)alkylphenyl or (C₁ -C₄)alkoxyphenyl. It is understood in the artthat such tautomeric forms exist in equilibrium and, depending on the R,R⁸, R⁷ etc. substituent, one form may be more favored in a givensubstitution pattern. It is also understood that portrayal of a giventautomer in a structure is for convenience only and that all tautomericforms are included in each such written structure.

This invention is further illustrated by the following examples.

EXAMPLE 1 Preparation of Ethyl2-Dimethylaminomethyl-4-thiazolecarboxylate

A reaction mixture was prepared containing 15.5 g. ofdimethylaminothioacetamide hydrochloride, 20.5 g. of ethyl bromopyruvateand 100 ml. of ethanol. The reaction mixture was heated to refluxingtemperature for about four hours after which time the solvent wasremoved in vacuo in a rotary evaporator. The residue, containing ethyl2-dimethylaminomethyl-4-thiazolecarboxylate formed in the abovereaction, was dissolved in a mixture of ether and water. The aqueouslayer was separated. The ether layer was extracted with an equal volumeof water and then discarded. The two aqueous layers were combined andwashed with ether. The ether layer was again discarded and the aqueouslayer cooled to a temperature in the range of 0°-5° C. Solid potassiumcarbonate was added until the aqueous layer gave a basic reaction tolitmus. An oil separated comprising ethyl2-dimethylaminomethyl-4-thiazolecarboxylate free base. The oily layerwas extracted with ether and the ether extract separated and dried. Theether was removed by evaporation in vacuo. The resulting residue waspurified by gradient high pressure liquid chromatography (silica ethylacetate). Ethyl 2-dimethylaminomethyl-4-thiazolecarboxylate thusobtained had the following physical characteristics:

Analysis Calculated: C, 50.45; H, 6.59; N, 13.07; S, 14.96. Found: C,50.13; H, 6.39; N, 12.89; S, 15.04.

The nmr spectrum in CDCl₃ (TMS internal standard) gave the followingsignals (δ): 1.43 (triplet, 3H), 2.40 (singlet, 6H), 3.87 (singlet, 2H),4.47 (quartet, 2H), 8.20 (singlet, 1H).

Following the above procedure, a solution containing 20.4 g. of ethylbromopyruvate and 20.8 g. of N-methyl-N-benzoyl thioacetamide in 100 ml.of ethanol was heated to refluxing temperature for about 4 hours. Thesolvent was removed by evaporation in vacuo and the resulting residuedissolved in 65 ml. of 4.5 N aqueous hydrochloric acid. The aqueousacidic layer was extracted with ether and the ether extract discarded.11.5 g. of sodium carbonate were added to the aqueous layer. Ethyl2-(methylbenzoylaminomethyl)-4-thiazolecarboxylate formed in the abovereaction, being insoluble in the solution, separated and was extractedinto ether. The ether extract was separated and dried. Evaporation ofthe ether yielded 20.2 g. of ethyl2-(methylbenzoylaminomethyl)-4-thiazolecarboxylate melting at about151.5°-153.5° C. after recrystallization from ethyl acetate.

Analysis Calculated: C, 59.19; H, 5.30; N, 9.20. Found: C, 58.98; H,5.25; N, 8.90.

The nmr spectrum in CDCl₃ (TMS internal standard) gave the followingsignals (δ): 1.42 (triplet, 3H), 3.07 (singlet, 3H), 4.41 (quartet, 2H),4.98 (singlet, 2H), 7.40 (apparent singlet, 5H), 8.16 (singlet, 1H).

EXAMPLE 2 Preparation of 2-Dimethylaminomethyl-4-thiazolemethanol

A solution of 12.5 g. of ethyl2-dimethylaminomethyl-4-thiazolecarboxylate dissolved in about 35 ml. ofanhydrous tetrahydrofuran was prepared and then cooled to about 0° C.under a nitrogen atmosphere. About 130 ml. of a 1 molar solution oflithium triethylborohydride in THF was added in dropwise fashion whilemaintaining the temperature in the range 0°-5° C. The reaction mixturewas stirred for about two hours after which time 36 ml. of 6 N aqueoushydrochloric acid were added while maintaining the temperature in therange -3° C. to 0° C. The volatile constituents were removed in vacuo ona rotary evaporator. Water was added to the resulting residue and againthe volatile constituents were removed. Water was again added to theresidue and the aqueous mixture extracted several times with ether. Theether extracts were separated and discarded. The aqueous solution wasthen chilled and made basic by the addition of solid potassiumcarbonate. The resulting alkaline aqueous mixture was extracted withethyl acetate. 2-Dimethylaminomethyl-4 -thiazolemethanol, beinginsoluble in the basic solution, separated and was extracted withseveral portions of ethyl acetate. The ethyl acetate extracts werecombined, and the combined extracts washed with saturated aqueous sodiumchloride and then dried. The ethyl acetate was removed by evaporation.The residue consisting of a brown oil weighing about 7.7 g. comprised2-dimethylaminomethyl-4-thiazolemethanol formed in the above reactionhaving the following physical characteristics.

Analysis Calculated: C, 48.81; H, 7.02; N, 15.26. Found: C, 48.71; H,6.77; N, 15.85.

The nmr spectrum in CDCl₃ (TMS internal standard) gave the followingsignals (δ): 2.33 (singlet, 6H), 3.74 (singlet, 2H), 4.32 (singlet, 1H),4.72 (singlet, 2H), 7.15 (singlet, 1H).

Boiling point=102° C. at 0.5 torr.

Following the above procedure, 22.5 g. of ethyl N-methyl-N-benzoyl2-aminomethyl-4-thiazolecarboxylate were dissolved in 125 ml. of dry THFunder a nitrogen atmosphere. 320 ml. of a 1 M LiEt₃ BH in THF was added.(Excess borohydride was required over the amount in the above examplebecause of the necessity of reducing both the ethyl ester group to ahydroxymethyl group and of removing the benzoyl group as benzyl alcoholleaving a secondary amine). The reaction mixture was worked up inaccordance with the above procedure by decomposition with 6 N aqueoushydrochloric acid and water. The residue remaining after the volatileconstituents had been removed was a thick oil which was taken up in alittle water and 60 ml. of ether. 1 ml. of 12 N aqueous hydrochloricacid was added, thus making the aqueous phase strongly acidic. The etherlayer was separated and the aqueous layer extracted five more times withequal portions of ether. The ether extracts were discarded. The waterlayer was separated and the water removed by evaporation in vacuo. Theacidic residue was made strongly basic (while being cooled) with 50%aqueous sodium hydroxide (6 grams in 6 ml. of water).2-Methylaminomethyl-4-thiazolemethanol produced by the above series ofreactions was insoluble in the alkaline layer and separated. Thecompound was taken up in ethyl acetate using a continuous extractor.Removal of the solvent left a tannish oily residue weighing 10.7 gramscomprising 2-methylaminomethyl-4-thiazolemethanol. The compound wasconverted to the dihydrochloride salt by standard laboratory procedures.

Alternatively, a mixture of 2.14 g of ethyl2-dimethylaminomethyl-4-thiazolecarboxylate and 0.38 g of sodiumborohydride in 20 ml. of isopropanol was heated with stirring at refluxtemperature for about 14 hours. The reaction mixture was cooled, and 2ml. of water were added carefully followed by 4 ml. of 5 N aqueoushydrochloric acid. The volatile constituents were removed byevaporation. Methanol (10 ml.) was added and the mixture heated torefluxing temperature for about one hour. Methanol was removed byevaporation and the residual solids digested in 10 ml. of isopropanol onthe steam bath. The isopropanol solution was separated by decantationand the solids reextracted with 10 ml. of isopropanol. The isopropanolsolutions and extracts were combined and the combined solution filteredwhile hot to remove insoluble material. The filtrate was chilled and acrystalline solid appeared which separated and was recovered byfiltration. Recrystallization of the filter cake from isopropanol gave1.73 g of 2-dimethylaminomethyl-4-thiazolemethanol hydrochloride meltingat 153°-154° C.

Analysis: calculated: C, 40.28; H, 6.28; Cl, 16.99; N, 13.42. Found: C,40.38; H, 5.04; Cl, 17.24; N, 13.12.

The methanols produced by the process of this example are readilyconverted to the corresponding thiazolemethyl chlorides according to thefollowing procedure: A suspension was prepared from 1.05 grams of2-dimethylaminomethyl-4-thiazolemethanol hydrochloride and 15 ml. ofchloroform. Thionyl chloride (2.50 g) was added and the resultingmixture was stirred at reflux temperature for about 2.75 hours. Anyvolatile constituents including excess thionyl chloride were removed byevaporation. The residue was suspended in chloroform and the chloroformremoved by evaporation. The residue was then recrystallized from amethanol-ethyl acetate solvent mixture to yield2-dimethylaminomethyl-4-thiazolymethylchloride hydrochloride melting at136°-8° C.

Analysis: calculated: C, 37.01; H, 5.32; Cl, 31.21; N, 12.33. Found: C,37.13; H, 5.06; Cl, 31.41; N, 12.36.

EXAMPLE 3 Preparation of2-(2-Dimethylaminomethyl-4-thiazolylmethylthio)ethylamine

A reaction mixture was prepared from 18.8 g. of2-dimethylaminomethyl-4-thiazolemethanol, 12.8 g. of 2-aminoethanethiolhydrochloride (cysteamine hydrochloride) and 160 ml. of 48% aqueoushydrobromic acid. The reaction mixture was stirred at about 100° C. forabout 11 hours. The volatile constituents were removed in vacuo on arotary evaporator. Water was added and the volatile constituents againremoved by evaporation. The resulting residue, comprising2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylaminetrihydrobromide formed in the above reaction, was dissolved in ethanol.The ethanol was evaporated and the resulting residue again dissolved inethanol. Evaporation of the ethanol yielded a hygroscopic residue whichwas recrystallized from a methanol-ethyl acetate solvent mixture.2-(2-Dimethylaminomethyl-4-thiazolylmethylthio)ethylaminetrihydrobromide thus prepared had the following physicalcharacteristics:

Analysis calculated: C, 22.80; H, 4.25; Br, 50.56; N, 8.86; S, 13.53.Found: C, 23.02; H, 4.31; Br, 50.64; N, 8.80; S, 13.60.

The nmr spectrum in DMSOd₆ (TMS internal standard) gave the followingsignals (δ): 2.55-3.2 (multiplet, 4H), 2.84 (singlet 6H), 3.92 (singlet,2H), 4.74 (singlet, 2H), 7.2-7.7 (broad, 1H), 7.94 (singlet, 1H), 7.92(broad, 3H), 10.22 (broad, 1H).

Following the above procedure, 10.1 millimoles of2-(methylaminomethyl)-4-thiazolemethanol dihydrochloride, 1.15 g. ofcysteamine hydrochloride and 15 ml. of 48% aqueous hydrobromic acid werestirred at about 100° C. for about 7.5 hours. Water and hydrobromic acidwere removed on a rotary evaporator and the resulting residue comprising2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine trihydrobromideformed in the above reaction was dissolved in water and the waterremoved by evaporation. The residue was again taken up in water and thewater removed by evaporation. The residue was then dissolved in a smallvolume of water and a solution of 5.5 g. of potassium carbonate in 15ml. of water was added. The resulting alkaline solution was evaporatedto dryness. The resulting residue, comprising the free base of2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine, was slurriedwith ethanol and the ethanol separated and removed by evaporation. Theresidue was twice slurried with isopropanol. The residue was nextextracted with boiling isopropanol several times and the combinedisopropanol extracts combined and filtered. Removal of the isopropanolyielded a yellow oil. The yellow oil was dissolved in chloroform and thechloroform solution filtered. Chloroform was evaporated from thefiltrate to yield 1.59 g. of a yellow oil comprising2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine. The compoundhad the following physical characteristics:

The nmr spectrum is CDCl₃ (TMS internal standard) gave the followingsignals (δ): 1.53 (overlapping singlets, 3H), 2.53 (singlet 3H), 2.62(triplet, 2H), 2.86 (triplet, 2H), 3.81 (singlet, 2H), 4.04 (singlet,2H), 7.04 (singlet, 1H).

The above primary amine can be prepared by an alternate procedureinvolving the fusion of a2-dialkylaminoalkyl-4-isothiazolylmethylchloride acid addition salt withan acid addition salt of cysteamine (or homocysteamine). This alternateprocedure is illustrated below.

2-Dimethylaminomethyl-4-thiazolylmethylchloride hydrochloride (1.92 g.)and cysteamine hydrochloride (0.96 g.) were intimately mixed and themixture heated slowly under anhydrous conditions to about 100° C. over aperiod of one hour. The reaction mixture was then heated in the range104°-110° C. for a period of 6 hours at which time the reaction wassubstantially complete as determined by tlc [silica-95:5 ethanol-NH₄ OH(0.88 sp. gr.)]. The reaction mixture was cooled and the cooled meltdissolved in a minimal amount of water. The solution was transferred toa rotary evaporator and the water removed. The resulting residuesolidified and the solid was recrystallized from a methanol-ethylacetate solvent mixture. Hygroscopic crystals of2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl aminetrihydrochloride thus produced melted at about 165°-72° C. withevolution of HCl.

Analysis calculated: C, 31.72; H, 5.91; Cl, 31.21; N, 12.33; S, 18.82.found: C, 31.63; H, 6.15; Cl, 31.34; N, 12.62; S, 18.63.

EXAMPLE 4 Preparation ofN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-cyanoguanidine

A solution was prepared from 3.07 g. of dimethylcyanodithioimidocarbonate and 35 ml. of ethanol. A second solutioncontaining 4.62 g. of2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine in 50 ml. ofethanol was added in dropwise fashion with stirring to the firstsolution over a period of about 1.5 hours. The resulting reactionmixture was stirred for an additional 20 hours after which time thevolatile constituents were removed in a rotary evaporator.Chromatography of the residue over silica by gradient elution usingethyl acetate containing increasing quantities of methanol as the eluantyielded fractions containing methylN-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-cyanocarbamidothioate,formed in the above reaction. These fractions were combined and thesolvent removed from the combined fractions in a rotary evaporator. Theresidue weighed 4.8 g. and, after recrystallization from carbontetrachloride, melted at about 75°-77° C.

Analysis Calculated: C, 43.74; H, 5.81; N, 21.25; S, 29.19. Found: C,43.46; H, 5.71; N, 20.98; S, 29.15.

2.52 g. Of the above thioester were dissolved in 12 ml. of methanol. 30ml. of a 35% solution of methylamine (w/w) in ethanol was added withstirring. After five hours, the solvent and excess amine were removed byevaporation on a rotary evaporator. The residue was purified by gradientelution chromatography (silica-ethyl acetate-methanol). FractionscontainingN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-cyanoguanidineformed in the above reaction were combined to yield 1.86 g. of a glassyresidue upon evaporation of the solvent.

Analysis Calculated: C, 46.13; H, 6.45; N, 26.90. Found: C, 46.43; H,6.39; N, 26.85.

The nmr spectrum in CDCl₃ (TMS internal standard) shows the followingsignals (δ): 2.34 (singlet, 6H); 2.72 (triplet, 2H); 2.84 (doublet, 3H);3.42 (multiplet, 2H); 3.74 (singlet, 2H); 3.82 (singlet, 2H); 6.08(multiplet, 1H); 6.22 (multiplet, 1H); 7.10 (singlet, 1H).

Following the above procedure, but substituting ethylamine formethylamine in the reaction withN-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-cyanocarbamidothioate,N-ethyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-cyanoguanidinewas prepared.

Analysis calculated for C₁₃ H₂₂ N₆ S₂ : C, 47.82; H, 6.79; N, 25.74; S,19.64. Found: C, 48.05; H, 7.01; N, 25.51; S, 19.33.

The nmr spectrum in CDCl₃ (TMS internal standard) shows the followingpeaks (δ): 1.22 (triplet, 3H), 2.34 (singlet, 6H), 2.72 (triplet, 2H),3.1-3.55 (multiplets unresolved, 4H), 3.74 (singlet, 2H), 3.82 (singlet,2H), 5.7 (broad, 1H), 6.0 (broad, 1H), 7.08 (singlet 1H).

EXAMPLE 5 Preparation ofN-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-methyl2-nitro-1,1-ethenediamine

A quantity of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylaminetrihydrobromide prepared from 50 g. of2-dimethylaminomethyl-4-thiazolylmethanol by the procedure of Example 3were dissolved in 150 ml. of water. A solution of 125 g. of potassiumcarbonate and 150 ml. of water was carefully added thereto. The waterwas removed by evaporation in vacuo. The resulting alkaline residue wastriturated with ethanol and isopropanol and the alkanols removedtherefrom by evaporation. The resulting residue was extracted severaltimes with hot isopropanol and the isopropanol extracts were filtered toremove inorganic salts. Evaporation of the solvent from the filtrateyielded a residue which was dissolved in chloroform and filtered. Thechloroform was removed from the filtrate on a rotary evaporator. Theresulting residue, comprising the free base of2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine, was dissolvedin 250 ml. of water. This solution was added to a stirred suspension of40.7 g. of N-methyl-1-methylthio-2-nitroethyleneamine (preparedaccording to the procedure of Belgian Pat. No. 859,388) at 50° C. Thesolution was stirred at the same temperature for about 4 hours after theaddition had been completed. Water was then removed by evaporation invacuo on a rotary evaporator. The resulting residue was dissolved inethanol and the solvent removed by evaporation. The residue wascrystallized from an ethanol-acetonitrile solvent mixture andrecrystallized from ethanol-ethyl acetate solvent mixture to yield 49.5g. of N-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl2-nitro-1,1-ethenediamine melting at about 130°-132° C.

Analysis Calculated: C, 43.48; H, 6.39; N, 21.13 O, 9.65. Found: C,43.66; H, 6.40; N, 21.14 O, 9.46.

The nmr spectrum in CDCl₃ (TMS internal standard) gave the followingsignals (δ): 2.24 (singlet, 6H), 2.68 (triplet, 2H), 2.74 (singlet, 3H),3.34 (multiplet, 2H), 3.70 (singlet, 2H), 4.84 (singlet, 2H), 6.46(singlet, 1H), 7.16 (broad, 1H), 7.40 (singlet, 1H), 9.96 (broad, 1H).

Following the above procedure,2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine andN-methyl-1-methylthio-2-nitroethyleneamine were reacted in watersolution. The reaction was worked up and the product isolated by theabove procedure to yieldN-methyl-N'-2-(2-methylaminomethyl-4-thiazolylmethylthio)ethyl2-nitro-1,1-ethenediamine metling at 105°-107° C. afterrecrystallization from acetonitrile followed by recrystallization fromethanol.

Analysis Calculated: C, 41.62; H, 6.03; N, 22.06 O, 10.08. Found: C,41.79; H, 6.10; N, 21.80; O, 10.28.

Following the above procedure,2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine was caused toreact with N-ethyl-1-methylthio-2-nitroethyleneamine to yieldN-ethyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl2-nitro-1,1-ethenediamine melting at about 89°-90° C.

Analysis Calculated for C₁₃ H₂₃ N₅ O₂ S₂ : C, 45.19, H, 6.71; N, 20.27;O, 9.26. Found: C, 45.32; H, 6.70; N, 20.44; O, 9.49.

EXAMPLE 6 Preparation ofN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylthiourea

A solution was prepared containing 0.80 g. of2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 0.29 g. ofmethylisothiocyanate in 10 ml. of ethanol. The solution was stirred atroom temperature for about 17 hours after which time the solvent wasremoved by evaporation in vacuo. The residual gum, comprisingN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylthioureaformed in the above reaction, was purified by chromatography over silicausing a gradient elution technique with ethyl acetate containingincreasing quantities of methanol as the eluant. Fractions containingthe above compound were combined and the solvent evaporated therefrom invacuo, leaving as a residue 0.83 g. of a glassy solid.

Analysis Calculated: C, 43.39; H, 6.62; N, 18.40 S, 31.59. Found: C,43.62; H, 6.49; N, 18.15; S, 31.70.

The nmr spectrum in CDCl₃ (TMS internal standard) gave the followingsignals (δ): 2.34 (singlet, 6H), 2.80 (triplet, 2H), 3.00 (doublet, 3H),3.74 (singlet, 2H), 3.82 (singlet, 2H), 3.6-3.9 (multiplet, 2H), 6.9(broad, 1H), 7.08 (singlet, 1H), 7.2 (broad, 1H).

Following the above reaction sequence, a solution of 0.93 g of2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine in 10 ml. ofanhydrous acetonitrile was prepared. A solution of 0.22 ml. of methylisocyanate in 5 ml. of anhydrous acetonitrile was added thereto. Thereaction was stirred at ambient temperature for about 2.5 hours at whichtime the solvent was removed by evaporation. The resulting residueslowly crystallized and was recrystallized from cylcohexane to yieldabout 0.97 g ofN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylureamelting at about 56°-59° C.

Analysis: calculated: C, 45.81; H, 6.99; N, 19.42; O, 5.55. found: C,46.03; H, 6.66; N, 19.41; O, 5.71.

EXAMPLE 7 Preparation ofN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-p-tolylsulfonylguanidine

A suspension was prepared by adding 1.35 g. of dimethylp-toluenesulfonylimidodithiocarbonate to 10 ml. of ethanol. While thesuspension was being stirred at ambient temperature, a solution of 1.16g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine in 10ml. of ethanol was added over a 15 minute period. The reaction mixturewas stirred for 2.5 hours after the addition had been completed. Thesolvent was then removed by evaporation in vacuo. The resulting residuewas mixed with 20 ml. of a 35% solution (w/w) of ethanolic methylamine.This reaction mixture was stirred for about 15 hours after which timethe solvent and other volatile constituents were removed by evaporationin vacuo. The residue was chromatographed over silica using a gradientelution technique employing ethyl acetate containing increasingquantities of methanol as the eluant. Fractions containingN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-p-tolylsulfonylguanidineformed in the above reaction were combined and the solvent removedtherefrom to leave as a residue 1.9 g. of a glass.

Analysis Calculated: C, 48.95; H, 6.16; N, 15.86; O, 7.25; S, 21.78.Found: C, 49.25; H, 6.27; N, 16.10; O, 7.45; S, 21.62.

The nmr spectrum in CDCl₃ (TMS internal standard) gave the followingsignals (δ): 2.34 (singlet, 6H), 2.38 (singlet, 3H), 2.62 (triplet, 2H),2.80 (doublet, 3H), 3.35-3.55 (multiplet, greater than 2H), 3.72(singlet, 2H), 3.74 (singlet, 2H), 7.06 (singlet, 1H), 7.18 (doublet,2H), 7.70 (doublet, 2H).

The above procedure was repeated using dimethylmethanesulfonylimidodithiocarbonate as a starting material.N-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-methanesulfonylguanidinewas obtained, m.p. 95°-97° C. after recrystallization from ethylacetate.

Analysis: calculated: C, 39.43; H, 6.34; O, 8.75. Found: C, 39.71; H,6.19; O, 8.72.

EXAMPLE 8 Preparation ofN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-nitroguanidine

A reaction mixture was prepared containing 1.2 g. of2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine, 0.77 g. ofS-methyl-N-methyl-N'-nitroisothiourea and 10 ml. of methanol. Thereaction mixture was heated under reflux for 4.25 hours, after whichtime the solvent was removed by evaporation. The partially solid residuewas chromatographed over silica using a gradient elution techniqueemploying ethyl acetate containing increasing quantities of methanol asthe eluant. Fractions shown by tlc to containN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-nitroguanidineformed in the above reaction were pooled and the solvent removed fromthe pooled fractions. Trituration of the resulting residue with etheryielded a crystalline solid which, upon recrystallization from amethanol-ethyl acetate solvent mixture, yielded 0.83 g. of crystalsmelting at about 86.5°-88° C.

Analysis Calculated: C, 39.74; H, 6.06; N. 25.28; O, 9.62; S, 19.29.Found: C, 39.92; H, 5.89; N, 25.15; O. 9.38; S, 19.49.

Following the above procedure,2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine was reactedwith S-methyl N-nitroisothiourea to yieldN-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-nitroguanidine.The compound was purified by chromatography (silica-ethylacetate/methanol), and melted at 104°-105.5° C. after recrystallizationfrom ethyl acetate.

Analysis: Calculated: C, 37.72; H, 5.70; N, 26.39; O, 10.05. Found: C,37.88; H, 5.41; N, 26.10; O, 10.34.

EXAMPLE 9 Preparation ofN-methyl-N'-2-(2-dimethylaminomethyl-5-methyl-4-thiazolylmethylthio)ethyl2-nitro-1,1-ethenediamine

Following the procedure of Example 1, a reaction mixture containing33.88 g,. of ethyl 2-oxo-3-bromobutyrate [prepared by the procedure ofSiefert et al., Helvi. Chim. Acta, 33, 725 (1950)], 21.52 g. ofdimethylaminothioacetamide hydrochloride and 100 ml. of anhydrousethanol was stirred and heated to refluxing temperature for about 2.5hours. The reaction mixture was allowed to remain at room temperatureovernight after which time it was concentrated by evaporation in vacuo.100 ml. of an ice-water mixture was added to the resulting residue andthe aqueous layer extracted with ethyl acetate. The ethyl acetate layerwas discarded. The aqueous layer was cooled and then made basic (pH=11)with 2 N aqueous sodium hydroxide. The resulting alkaline layer wasextracted several times with equal volumes of ethyl acetate and theethyl acetate extracts were combined. The combined extracts were washedwith water, with saturated aqueous sodium chloride, and were then dried.Concentration in vacuo provided a reddish oil comprising ethyl2-dimethylaminomethyl-5-methyl-4-thiazolecarboxylate. Yield=21.2 g.(57%).

Two hundred milliliters of a one molar solution of lithiumtriethylborohydride in THF were cooled in an ice bath under a nitrogenatmosphere. A solution of 21.2 g. of ethyl2-dimethylaminomethyl-5-methyl-4-thiazolecarboxylate in 60 ml. of THFwas added in dropwise fashion over about 1.5 hours. The reaction mixturewas maintained for an additional hour at 0° C. after which time it wasdecomposed by the cautious addition of 4 ml. of water plus 6 ml. of THFfollowed by 50 ml. of 6 N aqueous hydrochloric acid. The resultingreaction mixture was concentrated in vacuo and the residue treated withwater. Solid potassium carbonate was added to the aqueous mixture topH=11. The resulting aqueous alkaline mixture was extracted severaltimes with equal volumes of ethyl acetate. The ethyl acetate extractswere separated and combined and the combined extracts dried. The ethylacetate was removed therefrom in vacuo to leave, as a residue,2-dimethylaminomethyl-5-methyl-4-thiazolemethanol; yield=6.44 g. (44%).

Following the procedure of Example 3, a reaction mixture consisting of6.4 g. of ethyl 2-dimethylaminomethyl-5-methyl-4-thiazolemethanol, 4.2g. of cysteamine hydrochloride and 30 ml. of 48% aqueous hydrobromicacid was maintained at a temperature of about 100° C. under a nitrogenatmosphere for about 4 hours. The reaction mixture was cooled and thevolatile constituents removed in vacuo. The resulting dark residue wastwice trituated with ethanol and the ethanol removed by evaporation toremove residual HBr. The residue was then treated with 50 ml. of 5 Naqueous sodium hydroxide. The alkaline layer was continuously extractedwith ether over an 18 hour period. The ether extract was dried and theether removed therefrom in vacuo to provide2-(2-dimethylaminomethyl-5-methyl-4-thiazolylmethylthio)ethylamineprepared in the above reaction; yield=1.38 g. The compound was a brownoil having the following physical characteristics:

The nmr spectrum in CDCl₃ (TMS internal standard) shows the followingpeaks (δ): 1.48 (singlet, 2H), 2.35 (singlet, 6H), 2.42 (singlet, 3H),2.80 (multiplets, 4H), 3.72 (singlet, 2H), 3.80 (singlet, 2H).

Following the procedure of Example 5, a stirred solution of 1.38 g. of2-(2-dimethylaminomethyl-5-methyl-4-thiazolylmethylthio)ethylamine in 10ml. of methanol was treated withN-methyl-1-methylthio-2-nitroethyleneamine. The reaction mixture waskept at room temperature overnight by which time all solids haddissolved. Thin layer chromatography (silica-10:10:1 ethylacetate-methanol-ammonium hydroxide) indicated substantially a singleproduct. The reaction mixture was concentrated by evaporation of themethanol and the resulting gummy yellow residue was triturated withseveral portions of cold ether, thus providing an off-white gum.Repeated trituration with cold 1,2-dimethoxyethane yieldedN-2-(2-dimethylaminomethyl-5-methyl-4-thiazolylmethylthio)ethyl-N'-methyl-2-nitro-1,1-ethenediamineformed in the above reaction melting at about 104°-106° C.

Analysis Calculated: C, 45.19; H, 6.71; N, 20.27. Found: C, 45.54; H,6.47; N, 19.60.

The compound had the following physical characteristics:

The nmr spectrum in CDCl₃ (TMS internal standard) shows the followingpeaks (δ): 2.33 (singlet, 6H), 2.40 (singlet, 3H), 2.85 (multiplet, 2H),2.97 (doublet, 3H), 3.48 (multiplet, 2H), 3.68 (singlet, 2H), 3.82(singlet, 2H), 6.67 (singlet, 1H), 10.3 (broad, less than 2H).

EXAMPLE 10 Preparation ofN-4-(2-dimethylaminomethyl-4-thiazolyl)butyl-N'-methyl2-nitro-1,1-ethenediamine.

Following the procedure of Example 1, a stirred solution containing 3.2g. of dimethylaminothioacetamide hydrochloride, and 6.48 g ofbromomethyl 4-phthalimidobutyl ketone [prepared by the procedure ofChem. Listy., 49, 1385 (1955); C.A., 50, 5573c (1956)]; in 50 ml. ofethanol was heated at refluxing temperature for about 5 hours and wasthen cooled. Volatile constituents were removed by evaporation in vacuoleaving 2-dimethylaminomethyl-4-(4-phthalimido-1-butyl)thiazole as asemi-solid residue. The compound was utilized without furtherpurification.

A solution was prepared containing the above product in 50 ml. ofmethanol. While the solution was being stirred, 2 ml. of 85% hydrazinehydrate were added and the resulting mixture heated to refluxingtemperature for a about 2 hours. At this point, an additional 2 ml. of85% hydrazine hydrate were added and the heating continued for anadditional two hours. The reaction mixture was then diluted with 4volumes of water and the aqueous mixture made strongly basic withconcentrated aqueous sodium hydroxide. The resulting alkaline layer wasextracted continuously with ether for a 24 hour period. The etherextract was dried and the ether removed therefrom in vacuo to provide4-(2-dimethylaminomethyl-4-thiazolyl)butylamine as a brown oil;weight=1.81 g. (42% yield from bromoketone). Mass spectrum: m/e at 152,138, 128, 112, 96, 79, 71, 58, 42, 30 and 15.

A solution of 1.1 g. of the primary amine produced in the preceding stepin 15 ml. of methanol was stirred while a solution of 3.20 g. ofN-methyl 1-methylthio-2-nitroethyleneamine in methanolic solution wasadded thereto. The reaction mixture was maintained at room temperaturefor about 24 hours during which time evolution of methylmercaptan wasnoted. The progress of the reaction was followed by tlc. After thereaction had gone to completion according to tlc analysis, the volatileconstituents were removed in vacuo and the resulting residue dissolvedin a 9:1 ethyl acetate-methanol solvent mixture. This solution wasplaced on 15 g. of Woelm silica and the chromatogram developed with thesame solvent mixture. Fractions shown by tlc to containN-4-(2-dimethylaminomethyl-4-thiazolyl)butyl-N'-methyl2-nitro-1,1-ethenediamine formed in the above reaction was combined andthe solvent evaporated from the combined fractions in vacuo leaving aresidual gum. Repeated trituration of this gum with small volumes oftoluene followed by repeated recrystallization of the triturated solidfrom benzene provided off-white crystals melting at 97° -99° C.

Analysis Calculated: C, 49.82; H, 7.40; N, 22.35; S, 10.23. Found: C,49.56; H, 7.25; N, 22.12; S, 9.95.

The compound had the following peaks by mass spectral analysis: m/e at236, 212, 194, 178, 153, 126, 112, 97, 85, 71, 58, 42, 32 and 15.

EXAMPLE 11 Preparation ofN-methyl-N'-2-[2-(4-morpholinomethyl)-4-thiazolylmethylthio]ethyl2-nitro-1,1-ethenediamine

Following the procedure of Example 1, 4-morpholinothioacetamidehydrochloride was condensed with ethyl bromopyruvate to yield ethyl2-(4-morpholinomethyl)-4-thiazolecarboxylate, melting at 129°-130° C.after recrystallization from a methylene dichloride-ethyl acetatesolvent mixture.

Analysis Calculated: C, 51.54; H, 6.29; N, 10.93. Found: C, 51.36; H,6.05; N, 10.88.

Following the procedure of Example 2, the above ester was reduced to thecorresponding thiazolemethanol,2-(4-morpholinomethyl)-4-thiazolemethanol, having an nmr spectrum inCLDl₃ (TMS internaal standard) showing the following signals (δ): 2.55(multiplet, 4H), 3.35-3.90 (singlet plus multiplet, 6H), 4.70 (3H), 7.13(singlet, 1H).

Reaction of the thiazolemethanol with cysteamine hydrochloride by theprocedure of Example 3 yield2-[2-(4-morpholinomethyl)-4-thiazolylmethylthio]ethylamine having thefollowing physical characteristics:

nmr spectrum in CDCl₃ (TMS internal standard) showing the followingsignals (δ): 1.83 (singlet, 2H), 2.3-3.1 (multiplet, 8H), 3.4-3.9(multiplet plus singlets, 8H), 7.03 (singlet, 1H).

Following the procedure of Example 5, the2-[2-(4-morpholinomethyl)-4-thiazolylmethylthio]ethylamine was reactedwith N-methyl-1-methylthio-2-nitroethyleneamine to yieldN-methyl-N'-2-[2-(4-morpholinomethyl)-4-thiazolylmethylthio]ethyl-2-nitro-1,1-ethenediaminemelting at 151°-153° C. after recrystallization from a methanol-ethylacetate solvent mixture.

Analysis Calculated: C, 45.02; H, 6.21; N, 18.75. Found: C, 45.23; H,6.24; N, 18.56.

EXAMPLE 12 Preparation ofN-methyl-N'-2-[2-(1-pyrrolidinomethyl)-4-thiazolylmethylthio]ethyl2-nitro-1,1-ethenediamine

The same sequence of reactions as in Example 11 were carried outstarting with 1-pyrrolidinomethylthioacetamide hydrochloride to yieldthe following intermediates.

Ethyl 2-(1-pyrrolidino)-4-thiazolecarboxylate. M.P.=81°-81.5° C. afterrecrystallization from a toluene-ethyl acetate solvent mixture.

nmr spectrum in CDCl₃ (TMS internal standard) showed the followingsignals (δ): 1.40 (triplet 3H), 1.82 (multiplet, 4H), 2.70 (multiplet,4H), 4.02 (singlet, 2H), 4.45 (quartet, 2H), 8.17 (singlet, 1H).

2-(1-pyrrolidinomethyl)-4-thiazolemethanol. nmr spectrum in CDCl₃ (TMSinternal standard) gave the following signals (δ): 1.77 (multiplet, 4H),2.65 (multiplet, 4H), 3.92 (singlet, 2H), 4.73 (singlet, 3H), 7.15(singlet, 1H).

2-[2-(1-pyrrolidinomethyl)-4-thiazolyl-methylthio]ethylaminetrihydrobromide was crystallized from isopropanol.

The ethylamine obtained from the above hydrobromide was reacted withN-methyl-1-methylthio-2-nitroethyleneamine to yieldN-methyl-N'-2-[2-(1-pyrrolidinomethyl)-4-thiazolylmethylthio]ethyl2-nitro-1,1-ethenediamine melting at 119°-120° C. afterrecrystallization from a methanol-ethyl acetate solvent mixture.

Analysis calculated: C, 47.04; H, 6.49; N, 19.59. Found: C, 46.81; H,6.55; N, 19.04.

EXAMPLE 13 Preparation ofN-methyl-N'-2-[2-(1-piperidinomethyl)-4-thiazolylmethylthiolethyl2-nitro-1,1-ethenedianine

Following the sequence of reactins of Example 11, the followingintermediates were produced from 1-piperidinothioacetamidehydrochloride.

Ethyl 2-(1-piperidinomethyl)-4-thiazolecarboxylate melting at 95°-97° C.

nmr in CDCl₃ (TMS internal standard) gave the following signals (δ):1.40 (triplet, 3H), 1.53 (multiplet, 6H), 2.53 (multiplet, 4H), 3.85(singlet, 2H), 4.45 (quartet, 2H), 8.20 singlet, 1H).

2-(1-piperidinomethyl)-4-thiazolemethanol having an nmr spectrum inCDCl₃ (TMS internal standard) which gave the following signals (δ): 1.53(multiplet, 6H), 2.47 (multiplet, 4H), 3.77 (singlet, 2H), 4.77(singlet, >3H), 7.13 (singlet, 1H).

2-[2-(1-piperidinomethyl)-4-thiazolylmethylthio]ethylaminetrihydrobrmide crystallized from isopropanol. The nmr spectrum in DMSOd₆(TMS internal standard) showed the following signals (δ): 1.77(multiplet, 6H), 2.6-3.8 (8H, multiplets), 3.97 (singlet, 2H), 4.80(singlet, 2H), 7.80 (singlet, 1H), 8.12 (broad, 3H).

The primary amine obtained from the above salt was reacted with N-methyl1-methylthio-2-nitroethyleneamine to yieldN-methyl-N'-2-[2-(1-piperidinomethyl)-4-thiazolylmethylthio]ethyl2-nitro-1,1-ethenediamine melting at about 100°-103° C. afterrecrystallization from a methanol-ethyl acetate solvent mixture.

Analysis calculated: C, 48.49; H, 6.78; N, 18.85. Found: C, 48.72; H,6.94; N, 18.64.

EXAMPLE 14 Preparation ofN-methyl-N'-2-[2-methylethylaminomethyl)-4-thiazolylmethylthio]ethyl2-nitro-1,1-ethenediamine.

Following the reaction sequence of Example 11 starting with the reactionof N-methyl-N-ethyl aminothioacetamide hydrochloride and ethylbromopyruvate, the following intermediates were prepared:

Ethyl 2-(methylethylaminomethyl)-4-thiazolecarboxylate, anon-crystallizable oil

2-(methylethylaminomethyl)-4-thiazolemethanol having an nmr spectrum inCDCl₃ (TMS internal standard) showing the following signals (δ): 1.10(triplet, 3H), 2.33 (singlet, 3H), 2.53 (quartet, 2H), 3.80 (singlet,2H), 4.73 (singlet, 2H), 5.30 (singlet, 1H), 7.20 (singlet, 1H).

2-[2-(methylethylaminomethyl)-4-thiazolylmethylthio]ethylamine having annmr spectrum in CDCl₃ (TMS internal standard) showing the followingsignals (δ): 1.08 (triplet, 3H), 1.57 (singlet, 2H), 2.33 (singlet, 3H),2.2-3.0 (multiplets, 6H), 3.78 (apparent singlet, 4H), 7.03 (singlet,1H).

The above primary amine was reacted with N-methyl1-methylthio-2-nitroethyleneamine to yieldN-methyl-N'-2-[2-(methylethylaminomethyl)-4-thiazolylmethylthio]ethyl2-nitro-1,1-ethenediamine melting at 114°-116° C. afterrecrystallization from a methanolethyl acetate solvent mixture.

Analy sis calculated: C, 45.19; H, 6.71; N, 20.27. Found: C, 45.48; H,6.80; N, 19.98.

EXAMPLE 15 Preparation ofN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-aminocarbonylguanidine

Aout 0.6 g. ofN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-cyanoguanidinewere dissolved in 8 ml. of 1.5 N aqueous hydrochloric acid. Theresulting solution was allowed to remain at ambient temperature forabout four days. Volatile constituents were then removed by evaporationin vacuo. The resulting residue, comprisingN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-aminocarbonylguanidinedihydrochloride formed in the above reaction, was dissolved in ethanoland the ethanol removed by evaporation. The residue obtained thereby wasrecrystallized from isopropanol. The crystalline product was collectedand digested with ethyl acetate. The ethyl acetate was removed byevaporation and the product obtained was crystallized from isopropanolto yieldN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-aminocarbonylguanidinedihydrochloride melting at 156.5°-159.5° C.

Analysis Calculated for C₁₂ H₂₃ Cl₂ N₆ OS₂ : C, 35.82; H, 5.76; Cl,17.62; O, 3.98. Found: C, 35.64; H, 6.30; Cl, 17.73; O, 4.38.

EXAMPLE 16 Preparation ofN-(1-methylethyl)-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-cyanoguanidine.

A reaction mixture was prepared from 357 mg of silver nitrate, 3 ml ofisopropylamine and 12 ml of ethanol. To this stirred reaction mixturewas added a solution of 658 mg of methylN-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-cyanocarbamidothioate(from Example 4) and 15 ml. of ethanol. The reaction mixture was stirredat ambient temperature for about 18 hours after which time a precipitatewhich formed was separated by filtration. The filter cake was washedwith ethanol. Evaporation of the filtrate and the washings yielded aresidue which was chromatographed over silica using a gradient elutiontechnique. A solvent mixture containing 97.5% ethyl acetate and 2.5%methanol as the eluant eluted fractions containingN-(1-methylethyl)-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-cyanoguanidine.The compound was an oil.

Analysis: calculated: C, 49.38; H, 7.10; N, 24.68; S, 18.83. found: C,49.08; H, 7.19; N, 24.77; S, 18.62.

nmr (CDCl₃): δat 1.26 (d. 6H); 2.37 (s, 6H); 2.65 trip, 2H); 3.45 (db,of trip, 2H); 3.76 (s, 2H); 3.83 (s, 2H); 5.23 (d, 1H); 5.81 (trip, 1H);7.08 (s, 1H); 3.5-4.1 (multiplet, 1H)

EXAMPLE 17 Preparation ofN-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-(2-methoxyethyl)-2-nitro-1,1-ethenediamine

A reaction mixture was prepared containing 2.31 g of2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine, and 1.65 g of1-nitro-2,2-bis(methylthio)ethylene in 30 ml. of acetonitrile. Thereaction mixture was heated to reflux temperature for about four hoursafter which time the solvent was removed by evaporation. The resultingresidue was chromatographed over silica using ethyl acetate as theeluant. Fractions shown by tlc to contain the desired product werecombined and the solvent evaporated therefrom to yield1-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]-amino)-1-methylthio-2-nitroethylene(2.39 g.) Melting at about 68.5°-70.0° C. after recrystallization fromethyl acetate.

Analysis: Calculated: C, 41.36; H, 5.78; N, 16.08; S, 27.60. found: C,41,54; H, 5.61; N, 16.14; S, 27.54.

A reaction mixture, prepared from 1.25 g of1-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-1-methylthio-2-nitroethylene,0.27 g of 2-methoxyethylamine and 20 ml of ethanol, was heated torefluxing temperature for about three hours. The solvent was thenremoved by evaporation and the resulting residue was chromatographedover silica using a gradient elution technique. The desired compound waseluted with a 5:95 methanol:ethyl acetate solvent mixture. Removal ofthe solvent yieldedN-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-(2-methoxy)ethyl2-nitro-1,1-ethenediamine as an oil.

Analysis: calculated: C, 44.78; H, 6.71; N, 18.65; O, 12.78. found: C,44.65; H, 6.59; N, 18.32; O, 13.03.

nmr (CDCl₃): δ at 2.36 (s, 6H); 2.76 (trip, 2H); 3.40 (s, 3H); 3.1-3.65(multiplets, 6H); 3.75 (s, 2H); 3.83 (s, 2H); 6.54 (s, 1H); 6.75 (br,1H); 7.08 (s, 1H); 10.35 (br, 1H).

Following the above procedure,1-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-1-methylthio-2-nitroethylenewas reacted with a series of amines: 3-dimethylaminopropylamine,cyclopropylamine, 2-hydroxyethylamine, dimethylamine and ammonia toyield the following products:

N-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-(3-dimethylamino)propyl-2-nitro-1,1-ethenediamine(a glass).

Analysis: calculated: C, 47.74; H, 7.51; N, 20.88. found: C, 47.82; H,7.24; N, 21.16.

nmr (CDCl₃): δ at 1.77 (quintet, 2H); 2.23 (s, 3H); 2.28 (s, 3H); 2.36(2, 6H); 2.23-2.28 (underlying, 2H); 2.72 (trip, 2H); 3.0-3.5(multiplets, 4H); 3.75 (s, 2H); 3.84 (s, 2H); 6.50 and 6.53 (s, total1H); 7.11 (s, 1H); 8.6 (br, 1H); 10.2 (br. 1H).

N-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-cyclopropyl2-nitro-1,1-ethenediamine. Melting at 128.5°-131.5° C. afterrecrystallization from a methanol/ethyl acetate solvent mixture.

Analysis: calculated: C, 47.04; H, 6.49; N, 19.59. found: C, 47.31; H,6.12; N, 19.35.

N-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-(2-hydroxy)ethyl2-nitro-1,1-ethenediamine obtained as a glass, was eluted from a silicachromatographic column with a 94:5:1 ethyl acetate:methanol:ammoniumhydroxide (0.88 sp. gr.) solvent mixture as the eluant. R_(f) =0.43 onsilica using a 95:5 ethanol: ammonium hydroxide solvent mixture.

nmr (CDCl₃): δ at 2.37 (s, 6H); 2.80 (trip, 2H); 3.1-3.6 (multiplets,4H); 3.74 (s, 2H); 3.85 (s, 1H); ca. 3.8 (multiplet unresolved, 2H);6.58 (s, 1H); 7.11 (s, 1H); 7.80 (br, 1H); 10.36 (br, 1H).

N-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N',N'-dimethyl-2-nitro-1,1-ethenediamine.The compound was purified by chromatography over silica using a 95:5ethyl acetate:methanol solvent mixture as the eluent. The compound wasan oil.

Analysis: calculated: C, 45.19; H, 6.71; N, 20.27. found: C, 45.32; H,6.71; N, 20.54.

nmr (CDCl₃): δ at 2.36 (s, 6H); 2.79 (trip, 2H); 2.91 (s, 6H); 3.44 (db.of trip, 2H); 3.74 (s, 2H); 3.86 (s, 2H); 6.48 (s, 1H); 7.12 (s, 1H);9.46 (br, 1H).

N-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl2-nitro-1,1-ethanediamine melting at 125°-7° C. after purification bychromatography over silica using a 94:5:1 ethyl acetate-methanol-NH₄ OH(0.88 sp. gr.) solvent mixture as the eluant.

Analysis: calculated: C, 41.62; H, 6.03; N, 22.06. found: C, 41.38; H,6.21; N, 21.87.

EXAMPLE 18 Preparation ofN-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-cyanoguanidine.

A reaction mixture was prepared from 1.16 g of2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine, 0.45 g ofsodium dicyanamide, 4.8 ml 1N aqueous hydrochloric acid and 8 ml ofn-butanol. The reaction mixture was heated to reflux temperature forabout 16 hours and then was filtered. Evaporation of the filtrate todryness yielded a residue which was purified by chromatography oversilica using a 98:2 ethyl acetate:methanol solvent mixture as theeluant. Fractions shown by tlc to contain the desired product werecombined and the solvent evaporated therefrom.N-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-cyanoguanidinethus obtained was a glass.

Analysis: calculated: C, 44.27; H, 6.08; N, 28.16. found: C, 43.91; H,5.90; N, 27.93.

nmr (CDCl₃): δ at 2.32 (s, 6H); 2.76 (trip, 2H); 3.50 (db of trip, 2H);3.74 (s, 2H); 3.74 (s, 2H); 3.83 (s, 2H); 6.38 (br, 2H); 7.01 (s, 1H);7.64 (br, 1H).

EXAMPLE 19 Preparation ofN-3-(2-dimethylaminomethyl-4-thiazolylmethylthio)propyl-N'-methyl2-nitro-1,1-ethenediamine

Following the procedure of Example 3, 10 g of2-dimethylaminomethyl-4-thiazolylmethanol, 9.2 g of homocysteamine(3-aminopropanethiol) hydrobromide and 100 ml of 48% aqueous hydrobromicacid were heated to reflux temperature for about six hours. Volatileconstituents were removed by evaporation and the crystalline residue wastriturated with isopropanol. The isopropanol was decanted. Thisprocedure was repeated several times. The crystalline product wasfinally filtered to yield 7.0 g of3-(2-dimethylaminomethyl-4-thiazolylmethylthio)propylaminetrihydrobromide melting at 179°-181° C. (hygroscopic).

Analysis: calculated: C, 24.61; H, 4.54; Br, 49.11; N, 8.61. found: C,24.46; H, 4.34; Br, 49.31; N, 8.38.

A reaction mixture was prepared from 0.8 g of the abovethiazolylmethylthiopropylamine and 0.53 g of1-methylamino-1-methylthio-2-nitroethylene in 10 ml of ethanol. Thereaction mixture was heated to reflux temperature for about 20 hoursafter which time the solvent was removed by evaporation and theresulting residue triturated with ether.N-3-(2-dimethylaminomethyl-4-thiazolylmethylthio)propyl-N'-methyl2-nitro-1,1-ethenediamine thus prepared had the following physicalcharacteristics:

Analysis calculated: C, 45.19; H, 6.71; N, 20.27. found: C, 45.25; H,6.51; N, 19.99.

nmr (CDCl₃): δ at 1.93 (quintet, 2H); 2.42 (s, 6H); 2.65 (trip, 2H);2.92 (br, 3H); 3.34 (multiplet, 2H); 3.81 (s, 2H); 3.83 (s, 2H); 6.58(s, 1H); 7.10 (s, 1H).

EXAMPLE 20 Preparation of3-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-4-methylamino-3-cyclobutene-1,2-dione

A solution was prepared from 568 mg of3,4-dimethoxy-3-cyclobutene-1,2-dione and 15 ml of methanol. A secondsolution containing 925 mg of2-[2-(dimethylaminomethyl)-4-thiazolylmethylthio]ethyllamine in 25 ml ofmethanol was added to the first solution with stirring over a period ofabout 1.5 hours. After three hours a small amount of solid was removedfrom the reaction mixture by filtration. The filtrate was evaporated toa volume of about 10 ml and 6 ml of a 35% solution of methylamine inethanol was added thereto. After a reaction time of about 2.25 hours, asolid has separated. This solid was filtered and the filter cake washedwith methanol. Recrystallization of the filter cake from ethanol gave0.72 g of3-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-4-methylamino-3-cyclobutene-1,2-dionemelting at 163°-167° C.

Analysis: calculated: C, 49.39; H, 5.92; N, 16.46; O, 9.40. found: C,49.49; H, 6.01; N, 16.18; O, 9.59.

EXAMPLE 21 Preparation ofN-methyl-N'-2-[2-(3-dimethylamino)propyl-4-thiazolylmethylthio]ethyl-2-nitro-1,1-ethenediamine

A reaction mixture was prepared containing 95.2 g. of4-dimethylaminobutyronitrile, 134.3 g. of pyridine, 257.6 g. oftriethylamine and 113 g. of H₂ S. The reaction mixture was placed in anautoclave and the autoclave shaken for about 16 hours at 55° C. Thereaction mixture was then removed from the autoclave and the volatileconstituents removed by evaporation in vacuo. The resulting residuecomprising 4-dimethylaminothiobutyramide formed in the above reactionwas digested with about 1.5 l. of boiling ethyl acetate. The mixturethus produced was filtered through cellulose (hyflo supercel). Thefiltrate was concentrated until crystals appeared. The crystals wereseparated by filtration and the separated crystals washed with ethylacetate. Sixty grams of 4-dimethylaminothiobutyramide melting at about77° C. were obtained.

Analysis: calculated: C, 49.27; H, 9.65; N, 19.15. found: C, 49.07; H,9.59; N, 18.99.

A suspension was prepared from 14.6 g. of 4-dimethylaminothiobutyramidein 50 ml. of ethanol. The suspension was chilled. A cold solution of3.65 g. of anhydrous hydrogen chloride in 50 ml. of anhydrous ethanolwas added followed by 21.5 g. of ethyl bromopyruvate. The resultingreaction mixture was stirred at ambient temperature for about one hourand then was heated to refluxing temperature for an additional 2.25hours. The volatile constituents were removed by evaporation in vacuoand the resulting residue taken up in a mixture of water and diethylether. The aqueous layer was separated and the separated layer extractedwith several equal portions of ether. The aqueous solution was againchilled and then made basic (pH=10) by the addition of solid sodiumbicarbonate and sodium carbonate. Ethyl2-(3-dimethylamino)propyl-4-thiazolecarboxylate, being insoluble in thealkaline aqueous solution, separated and was extracted into ether. Theether extracts were combined and dried and the ether removed therefromby evaporation in vacuo yielding 21 g. of the carboxylate ester as anoil. The compound had the following physical characteristics.

Thin layer chromatography (silica-95:5 ethanol/ammonia solvent system):R_(f) =0.43.

nmr (CDCl₃ -TMS)δ: 1.46 (triplet, 3H); 2.27 (singlet, 6H); 1.8-2.6(multiplets, approx. 4H); 3.24 (triplet, 2H); 4.43 (quartet, 2H); 8.04(singlet, 1H).

Following the procedure of Example 2, ethyl2-(3-dimethylamino)propyl-4-thiazolecarboxylate was reduced with lithiumtriethylborohydride to yield2-(3-dimethylamino)propyl-4-thiazolemethanol as an oil. The compound hadthe following physical characteristics.

Thin layer chromatography, R_(f) =0.42 (silica-95:5 ethanol/ammoniumhydroxide solvent system).

nmr (CDCl₃ -TMS)δ: 2.15 (singlet, 6H); 1.62-2.50 (multiplets, approx.4H); 2.05 (triplet, 2H); 3.75 (very broad, approx. 1H); 4.65 (singlet,2H); 7.0 (singlet, 1H).

About 2.0 g. of the above 4-thiazolemethanol were dissolved in ethanolto which was added 0.36 g. of anhydrous hydrogen chloride in ethanol.The ethanol was removed by evaporation and the resulting residuetriturated with ethyl acetate. Crystallization occurred and the crystalswere separated by filtration. Recrystallization from a mixture ofmethanol and ethyl acetate gave2-(3-dimethylamino)propyl-4-thiazolemethanol hydrochloride melting at125°-127° C.

Analysis: calculated: C, 45.66; H, 7.24; N, 11.83. found: C, 45.38; H,7.39; N, 11.63.

A reaction mixture was prepared from 1.43 g. of the abovethiazolemethanol hydrochloride, an equal weight of thionyl chloride and35 ml. of chloroform. The reaction mixture was heated to refluxingtemperature with stirring for about 3.5 hours. The volatile constituentswere removed in vacuo and the crystalline residue was triturated withethyl acetate. The ethyl acetate suspension was filtered.Recrystallization of the filter cake from a mixture of methanol andethyl acetate yielded4-(chloromethyl)-N,N-dimethyl-2-thiazolepropanamine hydrochloridemelting at 149°-151° C.

Analysis: calculated: C, 42.36; H, 6.32; Cl, 27.78. found: C, 42.11; H,6.18; Cl, 27.57.

A reaction mixture was prepared from 1.35 g. of4:(chloromethyl)-N,N-dimethyl-2-thiazolepropanamine hydrochloride and0.60 g. of 2-aminoethanethiol hydrochloride. The reaction mixture washeated at about 105° C. and agitated with a magnetic stirrer for onehour. The reaction mixture which melted was kept at about 105° C. for anadditional 6.5 hours. Upon cooling, amorphous solid formed which wasdissolved in water and 0.8 g. of potassium carbonate in water added. Thewater was removed by evaporation. The resulting residue was trituratedwith ethanol and the ethanol removed by evaporation. Thetrituration-evaporation process was repeated twice with isopropanol. Theresidue was then extracted five times with 8 ml. portions of boilingisopropanol. The combined isopropanol extracts were filtered and theisopropanol removed by evaporation in vacuo. About 1.4 g. of2-[2-(3-dimethylamino)propyl-4-thiazolylmethylthio]ethylamine wereobtained as a glass. The compound had the following physicalcharacteristics.

Thin layer chromatography: R_(f) =0.21 (silica-95:5 ethanol/ammoniumhydroxide).

nmr (CDCl₃ -TMS) δ: 2.00 (quintet, 2H); 2.40 (singlet, 6H); 1.75-3.40(overlapping multiplets, more than 10H); 3.80 (singlet, 2H); 5.75(broad, 2.6H; 6.90 (singlet, 1H).

Following the procedure of Example 5,2-[2-(3-dimethylamino)propyl-4-thiazolylmethylthio]ethylamine wasreacted with N-methyl-1-methylthiol-2-nitroethyleneamine to yieldN-methyl-N'-2-[2-(3-dimethylamino)propyl-4-thiazolylmethylthio]ethyl2-nitro-1,1-ethenediamine as an oil. The compound had the followingphysical properties:

Thin layer chromatography: R_(f) =0.31 (silica-95:5 ethanol:NH₄ OH).

Analysis: calculated: C, 46.77; H, 7.01; N, 19.48. found: C, 46.64; H,7.08; N, 19.41.

EXAMPLE 22 Preparation ofN-methyl-N'-2-[2-(2-dimethylamino)ethyl-4-thiazolylmethylthio]ethyl2-nitro-1,1-ethenediamine

A reaction mixture was prepared from 22.4 g. ofN,N-dimethylcyanoacetamide, 21 ml. of liquid hydrogen sulfide and 1 ml.of triethylamine. The reaction mixture was placed in an autoclave andthe autoclave shaken at about 55° C. for about 12 hours. The reactionmixture was taken from the autoclave and the volatile constituentsremoved by evaporation. Ethanol was added to the residue, thus producinga crystalline solid. The solid was filtered and the filter cake washedwith cold ethanol. Twenty-one grams of3-amino-3-thioxo-N,N-dimethylpropanamide were obtained melting at111°-114° C. The compound had the following nmr (CDCl₃ +DMSOd₆)δ: 3.07(doublet, 6H); 3.82 (singlet, 2H); 9.1 (very broad, 1H).

A reaction mixture was prepared from 21 g. of3-amino-3-thioxo-N,N-dimethylpropanamide, 21 ml. of ethyl bromopyruvateand 200 ml. of ethanol. The reaction mixture was heated to refluxingtemperature for 1.5 hours after which time the ethanol was removed byevaporation. A crystalline solid remained which was triturated withethanol and again filtered. Recrystallization of the crude product fromethanol yielded 20.5 g. of ethyl2-dimethylaminocarbonylmethylene-4-thiazolecarboxylate hydrobromidemelting at about 150°-153° C. The compound had the following nmr(CDCl₃)δ: 1.43 (triplet, 3H); 3.10 (doublet, 6H); 4.45 (quartet, 2H);5.02 (singlet, 2H); 8.33 (singlet, 1H); 10.6 (singlet, 1H).

A solution was prepared from 20.5 g. of ethyl2-dimethylaminocarbonylmethylene-4-thiazolecarboxylate, hydrobromide, 50ml. of ethanol and 50 ml. of water. One hundred twenty-seven ml. of 1Naqueous sodium hydroxide were added and the resulting solution stirredfor about 24 hours at room temperature. The ethanol was then removed byevaporation. The aqueous layer was extracted with ether and the etherdiscarded. Sixty-three and one half ml. of 1N aqueous hydrochloric acidwere then added. The acidic aqueous solution was chilled overnight and acrystalline solid which precipitated comprising2-dimethylaminocarbonylmethylene-4-thiazolecarboxylic acid was separatedby filtration. The filter cake was washed with a small amount of coldwater. 7.85 g. of product were obtained melting at 187°-188° C. Anadditional 4.40 g. of2-dimethylaminomethylcarbonylmethylene-4-thiazolecarboxylic acid wereobtained from the mother liquor.

Analysis: calculated: C, 44.87; H, 4.70; N, 13.08. found: C, 44.60; H,4.76; N, 12.87.

A suspension of 4.28 g. of2-dimethylaminocarbonylmethylene-4-thiazolecarboxylic acid in 50 ml. ofTHF was kept at about 15° C. under a nitrogen atmosphere. 80 ml. of a 1Mborane solution in THF were added. The reaction mixture was stirred forthree hours at about 10° C. after which time it was cooled to 0° C. and10 ml. of methanol were added in dropwise fashion. The reaction mixturewas then allowed to remain overnight at room temperature. The volatileconstituents were removed by evaporation in vacuo. Twenty ml. ofmethanol and 10 ml. of 6N aqueous hydrochloric acid were added to theresidue. The resulting solution was heated to refluxing temperature on asteam bath for 1.5 hours. The methanol was then removed by evaporationand 4.5 g. of sodium bicarbonate were added to the remaining aqueoussolution. Water was removed from this solution in vacuo and the solidresidue triturated with ethanol. The ethanol was removed by evaporation.This trituration process was repeated twice using isopropanol. Theresidual solid was then extracted four times with boiling isopropanol.The isopropanol extracts were filtered and the isopropanol removed fromthe filtrate by evaporation. 4.1 g. of an oil comprising2-(2-dimethylamino)ethyl-4-thiazolemethanol were obtained. The compoundwas purified using high-pressure liquid chromatography over silica withethanol as the eluant. 0.9 g. of product were obtained having thefollowing nmr (CDCl₃ +DMSOd₆)δ: 1.42 (singlet, 6H); 2.7-3.4 (overlappingtriplets, 4H); 4.65 (singlet, 2H); 4.8 (broad, greater than 1H); 7.00(singlet, 1H).

Following the procedure of Example 2,2-(2-dimethylamino)ethyl-4-thiazolemethanol was converted to2-(2dimethylamino)ethyl-4-thiazolemethylchloride hydrochloride withthionyl chloride. Then folliwng the procedure of Example 3, the chloridehydrochloride was reacted with cysteamine hydrochloride to yield2-[2-(2-dimethylamino)ethyl-4-thiazolylmethylthio]-ethylamine which wasin turn converted by the method of Example 5 toN-methyl-N'-2-[2-(2-dimethylamino)ethyl-4-thiazolylmethylthio]ethyl2-nitro-1,1-ethenediamine having the following physical characteristics:

Mass spectrum: m/e 346.

nmr (DMSOd₆)δ: 2.15 (singlet, 6H); 2.5-3.5 (multiplets, more than 11H);3.80 (singlet, 2H); 6.40 (singlet, 1H); 7.25 (singlet, 1H); 6-7 (v.broad, 1H); 9.5 (v. broad, 1H).

EXAMPLE 23 Alternate preparation ofN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-cyanoguanidine

About 0.6 g of sodium were added to 50 ml. of dry ethanol under an N₂atmosphere, thus forming sodium ethylate in ethanol. 0.91 g ofN-methyl-N'-(2-thio)ethyl-N"-cyanoguanidine (prepared by the procedureof U.S. Pat. No. 4,093,621) dissolved in 10 ml. of anhydrous ethanol wasadded thereto and the resulting mixture stirred at room temperature forabout 1 hour. Next, 1.59 g of2-dimethylaminomethyl-4-thiazolylmethylchloride hydrochloride was addedthereto in portions over a 1 hour period. After the addition had beencompleted, the reaction mixture was stirred for an hour at roomtemperature and was then heated to refluxing temperature for anadditional hour. The ethanol was removed from the reaction mixture byevaporation and ethyl acetate plus water (10:1) were added to theresidue. The pH of the aqueous phase was adjusted to pH=8 with 1Naqueous hydrochloric acid. The ethyl acetate extract was separated andthe ethyl acetate removed by evaporation. The residue was subjected tohigh pressure liquid chromatography (silica-20:80 ethanol/ethylacetate). Fractions containing the desired product as shown by tlc werecombined and the solvent evaporated therefrom. 1.10 g ofN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-cyanoguanidinewere obtained. The physical properties were substantially identical withthose obtained in Example 4 for the same compound.

Analysis: Calculated: C, 46.13; H, 6.45; N, 26.90. found: C, 46.04; H,6.58; N, 26.63.

In flow chart A above, Compound I is a substituted aminothioacetamidehydrohalide of the structure ##STR36## Where the substituting groups arealkyl, the compounds are known as, for example,dimethylaminothioacetamide, diethylaminothioacetamide, etc. and can beprepared by the method of J. Org. Chem., (Russia), 6, 884 (1970) inEnglish.

Illustrated preparations are given below.

PREPARATION 1 Morpholinothioacetamide

A reaction mixture was prepared from 203 ml. each of triethylamine andpyridine plus 63 g. of morpholinoacetonitrile. Hydrogen sulfide asbubbled through the heated, stirred reaction mixture for about 2.5hours. Stirring was continued overnight at ambient temperature. The nextday, H₂ S was passed through the heated, stirred reaction mixture for anadditional 1.5 hours. At this point, the solvents were evaporated invacuo and the residue triturated with ether. The ether wasdiscarded andthe residue dissolved in ethanol. Crystalline morpholinothioacetamideprecipitated and was separated by filtration. Treatment of the filtratewith alcoholic hydrogen chloride yielded morpholinothioacetamidehydrochloride melting in the range 64°-80° C. See also J.A.C.S., 72,2804 (1950).

Following the above procedure but using piperidinoacetonitrile in placeof morpholinoacetonitrile, there was prepared piperidinothioacetamidehydrochloride melting at 166°-168° C., after recrystallization fromethylacetate. See also Helv. Chim. Act., 43, 659 (1960).

Yield 35 g. from 62 g. of piperidinoacetonitrile starting material.

Following the above procedure using 100 g. of pyrrolidinoacetonitrile,there were obtained 68.4 g. of pyrrolidinothioacetamide hydrochloride(new) melting at about 195°-197° C.

Analysis calculated: C, 39.88; H, 7.25; N, 15.50 S, 17.74. Found: C,39.66; H, 6.99; N, 15.76; S, 17.84.

Following the above procedure but using 49 g. ofmethylethylaminoacetonitrile, 200 ml. of triethylamine and 200 ml. ofbenzene, there was prepared N-methyl-N-ethylaminothioacetamidehydrochloride (new) melting at 115°-117° C.

The compounds of formula (I) in which B is NRR⁶ are potent H₂ -receptorantagonists and thus anti-ulcer agents. The relation of the H₂-receptors to mammalian gastric secretion is described in an article byBlack et al. Nature, 236, 385 (1972).

The following assay for H₂ -receptor blocking activity was employed.Female albino rats were treated with estrone 24 hours prior to theinitiation of the experiment. The rats were sacrificed and the uterinehorns removed therefrom and suspended at ambient temperatures inisolated organ baths containing De Jalon's solution. Afterequilibration, the uterine strips are exposed to 50 millimole aqueouspotassium chloride, which produces a sustained contraction. When theuterus is so contracted, histamine produces a dose-dependent H₂-receptor-mediated relaxation. A control dose-response curve tohistamine is constructed on each tissue. Following thorough washout ofthe histamine after obtaining the control dose-response curve, eachantagonist (the compounds of this invention) is added for 30 minutes ata concentration of 10⁻⁵ molar. The uterine strips are then contractedwith aqueous potassium chloride in the presence of the antagonist and asecond dose-response curve to histamine obtained. In the presence of acompetitive antagonist, the dose-response curve to histamine is shiftedin parallel to the right with no depression of the maximum relative tothe control curve. The dose ratio (DR) is calculated for eachconcentration of antagonist by dividing the ED₅₀ of histamine in thepresence of the competitive antagonist by the control ED₅₀ forhistamine. The dissociation constant (K_(B)) of the antagonist iscalculated from the dose-ratios by the following equation:

    K.sub.B =[antagonist]/(DR-1)

Cimetidine is included as an internal standard.

Results of the above assay carried out onN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl2-nitro-1,1-ethenediamine indicated that the compound had anapproximately 11 times higher affinity for the H₂ -receptors thancimetidine.N-Methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-cyanoguanidinehad an affinity of about 1.5 times greater than cimetidine. The K_(B)for the former compound in nanomolar conc. was found to be 87 ascompared to a K_(B) for cimetidine of 871 indicating a relative affinityof about 10 to 1 using a Schild plot.

A second assay for H₂ -receptor blocking activity employs the isolatedbullfrog gastric mucosa--see Warrick and Lin, Communications in Chem.Pathology and Pharmacology, 13, 149 (1976). The assay is carried out asfollows: The gastric mucosa of the bullfrog (Rana catesbeiana) isseparated from the musculature of the stomach and placed between a pairof Ussing chambers made of lucite. The chambers are filled with frogRinger solution and acid secretion is stimulated by addition ofhistamine to the serosal side of the mucosa at a final concentration of10⁻⁵ M/1. Acid output is automatically titrated to pH 4.5. After steadyresponse to 10⁻⁵ M/1 of histamine is established, the antagonist (acompound of this invention) is added to the serosal chamber and themaximal inhibition by each concentration of the H₂ -antagonist isrecorded. From the dose-response curve, the ED₅₀ of the drug iscalculated. The relative potency of each unknown antagonist iscalculated by dividing the ED₅₀ for cimetidine by the ED₅₀ of the drugin question.N-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl2-nitro-1,1-ethenediamine had a relative potency of 17.78 compared to1.0 for cimetidine.

An in vivo assay for antisecretory action of drugs on acid secretionutilizes gastric fistula dogs with vagally innervated gastric fistulaand vagally denervated Heidenhain pouch. In this procedure, asteady-state gastric secretion is produced by the iv infusion ofhistamine. The antisecretory drugs under test are given eitherintravenously by infusion over a 30 minute period or orally 75 min.prior to collection of gastric secretion from the fistula.N-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl2-nitro-1,1-ethenediamine was about 6.5 times as active as cimetidine bythe intravenous route and about 11.0 times as active orally using thisprocedure.

These last results indicate thatN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl2-nitro-1,1-ethenediamine and other compounds of this invention arebetter absorbed orally than cimetidine or other recently developedhistamine H₂ -antagonists. This greater oral absorption is alsoindicated by a relatively greater oral toxicity (compared to ivtoxicity) for the compounds of this invention. LD_(50's) have beendetermined for the above ethenediamine and for cimetidine as follows:For N-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl2-nitro-1,1-ethenediamine, the following LD_(50's) were obtained: mouseiv 265 mg/kg, mouse oral 1685 mg/kg; rat iv above 300 mg/kg, rat oral1680 mg/kg. Literature LD₅₀ 's for cimetidine are 150, 2600, 106 and5000 mg/kg respectively. The relative lack (relative to cimetidine) oftoxicity by the intravenous route of the compounds of this invention issurprising as is the greater oral absorption.

The above figures as to potency and toxicity indicate a favorabletherapeutic ratio for the compounds of this invention. Preliminary testsalso indicate that certain of the compounds of this invention have alonger duration of action than cimetidine.

In utilizing the compounds of this invention as antisecretory agents,either the parenteral or oral route of administration may be employed.

In one embodiment of the invention, there is provided a pharmaceuticalformulation which comprises as an active ingredient, a compound offormula XX in which B is NRR⁶, or a pharmaceutically-acceptable saltthereof, associated with one or more pharmaceutically-acceptablecarriers therefor. Orally-acceptable formulations such as capsules ortablets constitute the preferred mode of administration.

For oral dosage, a suitable quantity of a free base of this invention,or a pharmaceutically-acceptable salt thereof, is mixed with one or moreconventional excipients such as starch and the mixture placed intelescoping gelatin capsules or compressed into tablets each typicallycontaining from 100-400 mg. of active ingredients. The tablets may bescored if lower or divided dosages are to be used. For parenteraladministration via an iv infusion, an isotonic solution of a salt ispreferably employed although a soluble free base is also useful inisotonic preparations.

Because of the higher oral absorption and longer duration of action ofthe compounds of this invention, particularlyN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl2-nitro-1,1-ethenediamine, it is believed that oral administration ofabout 50-80 mg. three to four times a day will suffice to control acidsecretion in ulcer patients and thus alleviate ulcer symptoms.Generally, however, the compounds of this invention are administered tohumans orally in a daily dosage range of 140-800 mg. Smaller dosages atmore frequent intervals may also be employed. The preferred oral dosagerange is about 2--5 mg./kg./day of mammalian body weight, although adosage range of from 1-10 mg./kg./day can be used.

I claim:
 1. A pharmaceutical formulation in unit dosage form adapted fororal administration to achieve an antisecretory effect, comprising perdosage unit an antisecretorially-effective amount ofN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl2-nitro-1,1-ethenediamine or a pharmaceutically acceptable acid additionsalt thereof plus one or more pharmaceutical excipients.
 2. Apharmaceutical formulation according to claim 1 containing from 50-80mg. of active drug per dosage unit.
 3. A method for inhibiting gastricacid secretion in mammals which comprises administering to a mammal,whose gastric acid secretion is excessive and who is in need oftreatment, an antisecretorially-effective amount ofN-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl2-nitro-1,1-ethenediamine or a pharmaceutically acceptable acid additionsalt thereof.
 4. A method according to claim 3 in which from 140-350 mg.of drug per day are administered orally to humans.
 5. A method accordingto claim 3 in which the oral daily dose is from 2-5 mg./kg. of mammalianbody weight.
 6. A method according to claim 3 in which the antisecretorydrug is administered orally.
 7. A method according to claim 3 in whichthe antisecretory drug is administered parenterally.